Addressing the architecture, dynamics and activation mechanism of the CGRP receptor
Lead Research Organisation:
Aston University
Department Name: Sch of Life and Health Sciences
Abstract
G protein coupled receptors (GPCRs) are the largest family of proteins in the human genome and also the largest target for therapeutic drugs; thus they are of enormous scientific and practical interest. They are divided into a number of families. Of these, family-A is the best understood, but family-B includes receptors which are likely to be important in many disease states and so it is important to understand how these function, both to further our knowledge of fundamental biology and also for the design of new drugs.
Calcitonin gene-related peptide (CGRP) is found throughout the nervous system and is particularly important in regulating both the cardiovascular system (the heart and blood vessels) and also the immune system and inflammation. The receptor for CGRP is of special scientific interest as it involves a GPCR called CLR and also a second protein called RAMP1. RAMP1 is a member of a protein family that modulates a number of GPCRs of which the best characterised is CLR. CGRP is also likely to be important both in cardiovascular disorders and any disease that involves inflammation. The peptide is a major cause of migraine and drugs which block CGRP receptors have shown great promise in clinical trials; however, so far it has not been possible to use these clinically because of toxicity problems. Thus, there is an urgent need to develop new drugs that could act on CGRP receptors.
The CGRP receptor is made up of two parts. A portion called the transmembrane domain is found in the membranes of cells. This is connected to the extracellular domain, which is on the outside of cells. CGRP interacts with both parts of this structure and causes the transmembrane domain to change shape. This causes the receptor to interact with other proteins, leading to cell activation. We have a crystal structure of the part of the CGRP receptor that is on the outside of cells. Unfortunately, we do not know how CGRP binds to this, nor do we know how it binds to the transmembrane domain. This severely limits our understanding of the receptor and our ability to design drugs that could target it.
We have previously used experimental data from a technique known as site-directed mutagenesis to construct a computer model of the transmembrane domain of the CGRP receptor. This transmembrane domain is very similar to the transmembrane domains of two family-B GPCRs which were crystallised after our computer model was produced. This gives us confidence that our approach of combining experimental and computational methods is valuable. In this project, we intend to extend the approach to study how CGRP binds to both domains of the receptor and how this causes the receptor to become activated. We will use mutagenesis and also methods where we physically cross-link CGRP to the receptor to identify contact points. We will then use these to construct computational models, which we can refine through further experimentation. Using a computer, we can predict how the receptor shape will change when CGRP binds to it, so identifying the mechanism for receptor activation. This knowledge will be benefitial in the design of new drugs which can either block the receptor or promote its activation.
Calcitonin gene-related peptide (CGRP) is found throughout the nervous system and is particularly important in regulating both the cardiovascular system (the heart and blood vessels) and also the immune system and inflammation. The receptor for CGRP is of special scientific interest as it involves a GPCR called CLR and also a second protein called RAMP1. RAMP1 is a member of a protein family that modulates a number of GPCRs of which the best characterised is CLR. CGRP is also likely to be important both in cardiovascular disorders and any disease that involves inflammation. The peptide is a major cause of migraine and drugs which block CGRP receptors have shown great promise in clinical trials; however, so far it has not been possible to use these clinically because of toxicity problems. Thus, there is an urgent need to develop new drugs that could act on CGRP receptors.
The CGRP receptor is made up of two parts. A portion called the transmembrane domain is found in the membranes of cells. This is connected to the extracellular domain, which is on the outside of cells. CGRP interacts with both parts of this structure and causes the transmembrane domain to change shape. This causes the receptor to interact with other proteins, leading to cell activation. We have a crystal structure of the part of the CGRP receptor that is on the outside of cells. Unfortunately, we do not know how CGRP binds to this, nor do we know how it binds to the transmembrane domain. This severely limits our understanding of the receptor and our ability to design drugs that could target it.
We have previously used experimental data from a technique known as site-directed mutagenesis to construct a computer model of the transmembrane domain of the CGRP receptor. This transmembrane domain is very similar to the transmembrane domains of two family-B GPCRs which were crystallised after our computer model was produced. This gives us confidence that our approach of combining experimental and computational methods is valuable. In this project, we intend to extend the approach to study how CGRP binds to both domains of the receptor and how this causes the receptor to become activated. We will use mutagenesis and also methods where we physically cross-link CGRP to the receptor to identify contact points. We will then use these to construct computational models, which we can refine through further experimentation. Using a computer, we can predict how the receptor shape will change when CGRP binds to it, so identifying the mechanism for receptor activation. This knowledge will be benefitial in the design of new drugs which can either block the receptor or promote its activation.
Technical Summary
The CGRP receptor is a particularly interesting family B G-protein coupled receptor (GPCR) having an absolute requirement for an auxiliary protein known as Receptor activity modifying protein 1 (RAMP1). Class B GPCRs consist of a large extracellular domain (ECD) and a transmembrane domain (TMD). They frequently associate with accessory proteins belonging to the family of RAMPs. They act as receptors for a number of peptide hormones and neurotransmitters. They are attractive therapeutic targets but it has proved very difficult to obtain drugs that target them. Several crystal structures exist for the ECDs and there are crystal structures for two class B GPCRs (glucagon and CRF), but neither have bound peptides and the orientation between the TMD and ECD for any receptor remains speculative, as does the mechanism whereby agonists activate the receptors.
We have recently used a combination of site-directed mutagenesis and molecular modelling to propose a structure for CGRP bound to the TMD of CLR. This shows excellent agreement with the crystal structures, which were published after our modelled structures were deposited. Thus we propose that our methodology is robust. Furthermore, the presence of the RAMP provides additional constraints on the orientation of the ECD relative to the TMD, making the CGRP receptor especially amenable to modelling by greatly reducing the number of ways in which it could be modelled incorrectly.
We propose a strategy of photoaffinity cross-linking, disulphide trapping and point mutagenesis to provide experimental information on the architecture of the receptor when bound to CGRP and as a test for the modelling. This information will then be used to produce a model of the complex. We will use molecular dynamics and other modelling techniques to plan the experiments, to interpret the results and hence to determine the conformational changes caused by CGRP binding and so establish how the receptor is activated by its native agonist.
We have recently used a combination of site-directed mutagenesis and molecular modelling to propose a structure for CGRP bound to the TMD of CLR. This shows excellent agreement with the crystal structures, which were published after our modelled structures were deposited. Thus we propose that our methodology is robust. Furthermore, the presence of the RAMP provides additional constraints on the orientation of the ECD relative to the TMD, making the CGRP receptor especially amenable to modelling by greatly reducing the number of ways in which it could be modelled incorrectly.
We propose a strategy of photoaffinity cross-linking, disulphide trapping and point mutagenesis to provide experimental information on the architecture of the receptor when bound to CGRP and as a test for the modelling. This information will then be used to produce a model of the complex. We will use molecular dynamics and other modelling techniques to plan the experiments, to interpret the results and hence to determine the conformational changes caused by CGRP binding and so establish how the receptor is activated by its native agonist.
Planned Impact
The chief beneficiaries will include industrial scientists who are seeking to develop new drugs and the companies which employ them. In turn this would have economic benefits for the UK and also enhance the quality of life from anyone who might receive such drugs (which would further benefit the UK economy).
The most immediate beneficiaries would be those companies with research programmes directed towards the development of CGRP antagonists for migraine, where there is clinical evidence of the effectiveness of these agents. Migraine alone is estimated to cost the UK economy £2.25 billion per annum (Steiner TJ., Lecture to the All Party Parliamentary Group on Primary Headache Disorders., 19 November 2008) and CGRP antagonists have been shown to be effective against migraine in clinical trials. There have been 66 new patent applications filed worldwide for CGRP antagonists since January 2010. Thus the development of new agents to target the CGRP receptor would be of considerable benefit both to the UK pharmaceutical industry and also the health and well-being of the UK population. The mode of binding of CGRP and the way it activates its receptor is likely to be shared by other peptides in this family such as amylin (implicated in the control of eating) and calcitonin (well-established for the treatment of osteoporosis), further adding to the value of the project. The spectrum of disorders covered by the CGRP family of peptides include many which are common amongst elderly populations (e.g. heart failure, osteoporosis) and so this project is relevant to the BBSRC's initiative on lifelong health and well-being. More broadly, the challenges resulting from CLR modelling have serendipitously resulted in the generation of a helix alignment program that can work below the "twilight zone" to align distantly related proteins (Vohra et al., J. Roy. Soc. 2013, Taddese et al., Plant Phys 2014) and we expect other methodologies to result from this challenging problem. Here, the way in which the modelling is closely integrated with experiment be applicable to a wide range of proteins of pharmaceutical or other interest. These include G-protein coupled receptors but extend far beyond those. In this respect, the project also addresses the BBSRC initiative on Technology development for the biosciences.
The most immediate beneficiaries would be those companies with research programmes directed towards the development of CGRP antagonists for migraine, where there is clinical evidence of the effectiveness of these agents. Migraine alone is estimated to cost the UK economy £2.25 billion per annum (Steiner TJ., Lecture to the All Party Parliamentary Group on Primary Headache Disorders., 19 November 2008) and CGRP antagonists have been shown to be effective against migraine in clinical trials. There have been 66 new patent applications filed worldwide for CGRP antagonists since January 2010. Thus the development of new agents to target the CGRP receptor would be of considerable benefit both to the UK pharmaceutical industry and also the health and well-being of the UK population. The mode of binding of CGRP and the way it activates its receptor is likely to be shared by other peptides in this family such as amylin (implicated in the control of eating) and calcitonin (well-established for the treatment of osteoporosis), further adding to the value of the project. The spectrum of disorders covered by the CGRP family of peptides include many which are common amongst elderly populations (e.g. heart failure, osteoporosis) and so this project is relevant to the BBSRC's initiative on lifelong health and well-being. More broadly, the challenges resulting from CLR modelling have serendipitously resulted in the generation of a helix alignment program that can work below the "twilight zone" to align distantly related proteins (Vohra et al., J. Roy. Soc. 2013, Taddese et al., Plant Phys 2014) and we expect other methodologies to result from this challenging problem. Here, the way in which the modelling is closely integrated with experiment be applicable to a wide range of proteins of pharmaceutical or other interest. These include G-protein coupled receptors but extend far beyond those. In this respect, the project also addresses the BBSRC initiative on Technology development for the biosciences.
Organisations
- Aston University (Lead Research Organisation)
- UNIVERSITY OF OXFORD (Collaboration)
- University of Rochester (Collaboration)
- UNIVERSITY OF NOTTINGHAM (Collaboration)
- Heptares Therapeutics Ltd (Collaboration)
- Medicines Discovery Catapult (Collaboration)
- University of North Carolina at Chapel Hill (Collaboration)
- University of Warwick (Collaboration)
- Johnson Matthey (United Kingdom) (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- IMPERIAL COLLEGE LONDON (Collaboration)
- Monash University (Collaboration)
Publications
Weaver RE
(2017)
High affinity binding of the peptide agonist TIP-39 to the parathyroid hormone 2 (PTH2) receptor requires the hydroxyl group of Tyr-318 on transmembrane helix 5.
in Biochemical pharmacology
Dal Maso E
(2018)
Extracellular loops 2 and 3 of the calcitonin receptor selectively modify agonist binding and efficacy.
in Biochemical pharmacology
Woolley MJ
(2017)
Receptor activity-modifying protein dependent and independent activation mechanisms in the coupling of calcitonin gene-related peptide and adrenomedullin receptors to Gs.
in Biochemical pharmacology
Bailey S
(2019)
Interactions between RAMP2 and CRF receptors: The effect of receptor subtypes, splice variants and cell context.
in Biochimica et biophysica acta. Biomembranes
Hay DL
(2018)
Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25.
in British journal of pharmacology
Wootten D
(2016)
The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism.
in Cell
Simms J
(2019)
The Structure of the CGRP and Related Receptors.
in Handbook of experimental pharmacology
Description | Wehave developed a method for photoaffinity labelling CGRP bound to the receptor. We have confirmed that a series of residues we predict that are close to the peptide binding site can cross-link to the ligand and have identified contacts within the probable binding pocket for CGRP in the transmembrane domain. We have confirmed the proximity of these reagents to the ligand binding site by changing these in the naturally occurring protein and shown that they disrupt the function of the receptor. We have also developed new computer methods to study how CGRP changes the shape of the protein to activate it and how the attachment of sugars contributes to the role of the allied calcitonin receptor. |
Exploitation Route | These findings open the way to the design of novel therapeutic agents, particularly for the treatment of migraine, hypertension and multiple sclerosis. The computer modelling methods we have developed may be of more general use in designing drugs specific for other receptors. Our findings also indicate the contribution of dynamic allostery to the functioning of receptors. |
Sectors | Pharmaceuticals and Medical Biotechnology |
URL | https://research.aston.ac.uk/en/persons/david-poyner |
Description | We have obtained a BBSRC IPA to produce antibody to RAMP-receptor complexes, in collaboration with UCB. We are working on in-silico methods of protein modelling with MD Catapult |
First Year Of Impact | 2018 |
Sector | Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | BBRSRC Responsive mode grant |
Amount | £27,991 (GBP) |
Funding ID | BB/R016755/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2018 |
End | 08/2021 |
Description | BBSRC Pathfinder |
Amount | £12,000 (GBP) |
Funding ID | BB/S000100/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 05/2018 |
End | 09/2018 |
Description | Internal PhD studentship |
Amount | £30,000 (GBP) |
Organisation | Aston University |
Department | School of Life and Health Sciences |
Sector | Academic/University |
Country | United Kingdom |
Start | 08/2016 |
End | 08/2019 |
Description | Pancreatic cancer UK |
Amount | £74,285 (GBP) |
Funding ID | RPG-2017-255 |
Organisation | Pancreatic Cancer UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2017 |
End | 02/2018 |
Description | Royal Society Industrial Fellowships |
Amount | £151,861 (GBP) |
Funding ID | IF160090 |
Organisation | The Royal Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2017 |
Description | Royal Society Summer Studentship |
Amount | £2,000 (GBP) |
Organisation | The Royal Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 07/2017 |
End | 09/2017 |
Title | Method for generating GPCR models |
Description | We have published a method for generating class B G protein-coupled receptor (GPCR) structures from X-ray, NMR or homology modelled sub-structures that is particularly suited to the 2 domain extracellular domain (ECD)/transmembrane (TM) structure of class B GPCRs. The essential feature is to generate partially overlapping fragments, which can be achieved through carefully docking of the full peptide ligand to both the ECD and the TM domain. The method also involves a two-step approach to handing photoaffinity labelling by first generating the model containing the labels in the presence of constraints and then translating the constraints into equivalent constraints for the wild-type receptor. The method is described in a series of 2016 publications, including: Wootten, D.; Reynolds, C. A.; Smith, K. J.; Mobarec, J. C.; Koole, C.; Savage, E. E.; Pabreja, K.; Simms, J.; Sridhar, R.; Furness, S. G.; Liu, M.; Thompson, P. E.; Miller, L. J.; Christopoulos, A.; Sexton, P. M. The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism. Cell 2016, 165, 1632-43. Weston, C.; Winfield, I.; Harris, M.; Hodgson, R.; Shah, A.; Dowell, S. J.; Mobarec, J. C.; Woodlock, D. A.; Reynolds, C. A.; Poyner, D. R.; Watkins, H. A.; Ladds, G. Receptor Activity-modifying Protein-directed G Protein Signaling Specificity for the Calcitonin Gene-related Peptide Family of Receptors. J. Biol. Chem. 2016, 291, 21925-21944. |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2016 |
Provided To Others? | Yes |
Impact | The method was taken up by Heptares Therapeutics and was used to model a particular receptor (by Dr Conor Scully) as part of a drug design program. This enabled the programme to get off to a good start and the programme is progressing well. As a result, a REF impact case is being prepared. |
Title | Transition state analysis |
Description | We have developed an in-silico method to predict the pathway of GPCR activation; this resulted in a Pathfinder award to DRP |
Type Of Material | Biological samples |
Year Produced | 2018 |
Provided To Others? | No |
Impact | We are currently working with MD Catapault to evaluate the utility of this method for drug discovery |
Title | CGRP |
Description | Computer models of the CGRP receptor have been deposited in the Essex Research Repository and are given a DOI from the relevant publications |
Type Of Material | Computer model/algorithm |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | Deeper understanding into the structure and function of the CGRP receptor that may be relevant to drug design and heart disease/migraine. |
URL | http://repository.essex.ac.uk |
Title | CTR/AMY |
Description | Molecular models of the calcitonin receptor (CTR) and the Amylin Receptor (AMY1R, i.e. CTR in complex with a receptor activity modifying protein). These models are stored in the Essex Research Repository and are referenced from associated publications / articles submitted. |
Type Of Material | Computer model/algorithm |
Year Produced | 2018 |
Provided To Others? | No |
Impact | Deeper understanding into the structure and dynamics of these calcitonin-based receptor models that are related to various diseases including osteoporosis, migraine and diabetes. |
URL | http://repository.essex.ac.uk/ |
Title | Data molecular dynamic simulations of CTR in "Calcitonin receptor N-glycosylation enhances peptide hormone affinity by controlling receptor dynamics" |
Description | NULL |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Title | Data underpinning article "Photoaffinity cross-linking and unnatural amino acid mutagenesis reveal insights into calcitonin gene-related peptide binding to the calcitonin receptor-like receptor/receptor activity-modifying protein 1 (CLR/RAMP1) complex" |
Description | NULL |
Type Of Material | Database/Collection of data |
Year Produced | 2018 |
Provided To Others? | Yes |
Title | GLP-1R |
Description | Computer models have been generated of the GLP-1 receptor, the adrenomedullin receptor and the PTH2 receptor; these have been validated by collaborative experimental studies. The models are available from ftp.essex.ac.uk/pub/oyster/ |
Type Of Material | Database/Collection of data |
Year Produced | 2016 |
Provided To Others? | Yes |
Impact | The models have had a significant impact on explaining pharmacological data on important drug targets, as indicated in the following publications: 1. Wotten, D., Reynolds, C. A., Smith, K. J., Mobarec, J. C., Koole, C., Savage, E. E., Pabreja, K., Simms, J., Sridhar, R., and Furness, S. G., Miller, L. J., Christopoulos, A., and Sexton, P. M. (2016) The extracellular surface of the GLP-1 receptor is a molecular trigger for biased agonism. Cell 165,1632-1643. doi.org/10.1016/j.cell.2016.05.023 2. Wootten, D., Reynolds, C. A., Smith, K. J., Mobarec, J. C., Furness, S. G., Miller, L. J., Christopoulos, A., and Sexton, P. M. (2016) Key interactions by conserved polar amino acids located at the transmembrane helical boundaries in Class B GPCRs modulate activation, effector specificity and biased signalling in the glucagon-like peptide-1 receptor. Biochem. Pharmacol. 118,68-87. doi.org/10.1016/j.bcp.2016.08.015 3. Wootten, D., Reynolds, C. A., Koole, C., Smith, K. J., Mobarec, J. C., Simms, J., Quon, T., Coudrat, T., Furness, S. G., and Miller, L. J. (2016) A hydrogen-bonded polar network in the core of the glucagon-like peptide-1 receptor is a fulcrum for biased agonism: lessons from class B crystal structures. Mol. Pharmacol. 89,335-347. doi.org/10.1124/mol.115.101246 4. Weston, C., Winfield, I., Harris, M., Hodgson, R., Shah, A., Dowell, S. J., Mobarec, J. C., Woodlock, D. A., Reynolds, C. A., and Poyner, D. R. (2016) Receptor Activity-modifying Protein-directed G Protein Signaling Specificity for the Calcitonin Gene-related Peptide Family of Receptors. J. Biol. Chem. 291,21925-21944. doi.org/10.1074/jbc.M116.751362 5. Weaver, R. E., Mobarec, J. C., Wigglesworth, M. J., Reynolds, C. A., and Donnelly, D. (2016) High affinity binding of the peptide agonist TIP-39 to the parathyroid hormone 2 (PTH 2) receptor requires the hydroxyl group of Tyr-318 on transmembrane helix 5. Biochem. Pharmacol. doi.org/10.1016/j.bcp.2016.12.013 6. Watkins, H. A., Chakravarthy, M., Abhayawardana, R. S., Gingell, J. J., Garelja, M., Pardamwar, M., McElhinney, J. M., Lathbridge, A., Constantine, A., and Harris, P. W. (2016) Receptor Activity-modifying Proteins 2 and 3 Generate Adrenomedullin Receptor Subtypes with Distinct Molecular Properties. J. Biol. Chem. 291,11657-11675. doi.org/10.1074/jbc.M115.688218 |
URL | http://ftp.essex.ac.uk/pub/oyster/ |
Description | CLR and congenital birth defects |
Organisation | University of North Carolina at Chapel Hill |
Country | United States |
Sector | Academic/University |
PI Contribution | We have modelled a naturally occurring mutated form of the calcitonin receptor-like receptor which prevents its association with birth defects and leads to fatal birth defects |
Collaborator Contribution | Our partners identified the initial birth defect in clinical studies and have explored its phenotype in cellular and whole-organism models. |
Impact | Paper in preparation |
Start Year | 2017 |
Description | Discovery Catapault |
Organisation | Medicines Discovery Catapult |
Country | United Kingdom |
Sector | Private |
PI Contribution | We will assess in-silico the activity of compounds where Discovery have details of activity |
Collaborator Contribution | Discovery hold experimental details of pharmacologically active compounds which we can assess using our software |
Impact | None so far |
Start Year | 2018 |
Description | FCS to study SMALPed proteins |
Organisation | University of Nottingham |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have supplied SMALP-purified adenosine 2a receptor for analysis by fluorescence correlation spectroscopy (FCS) by Dr Steve Briddon at Nottingham University |
Collaborator Contribution | Dr Briddon has performed and interpreted the FCS |
Impact | We have shown that it is possible to identify single molecules of the adenosine A2a receptor by FCS |
Start Year | 2017 |
Description | GLP-1 signalling and bias (with Imperial) |
Organisation | Imperial College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Preliminary data on the structure of the GLP-1 receptor (GLP-1R) Dynamics data for joint publication: Pickford et al., Partial agonism improves the anti-hyperglycaemic efficacy of an oxytomodulin-derived GLP-1R/GCGR co-agonist, Molecular metabolism, 51, 101242. |
Collaborator Contribution | Preliminary data on identification of biased ligands for GLP-1R Pharmacology data for joint publication: Pickford et al., Partial agonism improves the anti-hyperglycaemic efficacy of an oxytomodulin-derived GLP-1R/GCGR co-agonist, Molecular metabolism, 51, 101242. |
Impact | Award of an MRC grant entitled XXX on GLP-1R signalling and bias, (PI: , Co-Is: ); CAR was very pleased to supply a letter of support |
Start Year | 2017 |
Description | Mass spectroscopy of GPCRs |
Organisation | University of Oxford |
Department | Department of Chemistry |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have supplied purified GPCRs |
Collaborator Contribution | The partners are analysing the GPCRs by mass spectroscopy |
Impact | This is an academic collaboration; we hope it will lead to new papers |
Start Year | 2015 |
Description | Modelling remote homologues (with Johnson Matthey) |
Organisation | Johnson Matthey |
Country | United Kingdom |
Sector | Private |
PI Contribution | Sequence alignment in the twilight zone in the context of modelling remote homologues for building models of enzymes required for carrying out chemical reactions |
Collaborator Contribution | Supplied sequences |
Impact | alignments |
Start Year | 2018 |
Description | Modelling the Adenosine Receptor |
Organisation | University of Cambridge |
Department | Department of Pharmacology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Molecular modelling of the adenosine A1 receptor |
Collaborator Contribution | Molecular pharmacology of the A1 receptor In vivo testing of adenosine A1 agonists as analgesics without cardiovascular side effects Synthesis of novel adenosine A1 agonists |
Impact | multi-disciplinary: molecular modelling and experimental pharmacology |
Start Year | 2017 |
Description | Modelling the Adenosine Receptor |
Organisation | University of Warwick |
Department | School of Life Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Molecular modelling of the adenosine A1 receptor |
Collaborator Contribution | Molecular pharmacology of the A1 receptor In vivo testing of adenosine A1 agonists as analgesics without cardiovascular side effects Synthesis of novel adenosine A1 agonists |
Impact | multi-disciplinary: molecular modelling and experimental pharmacology |
Start Year | 2017 |
Description | Role of RCP in promoting signalling at GPCRs |
Organisation | University of Rochester |
Country | United States |
Sector | Academic/University |
PI Contribution | We have been examining the ability of receptor component protein (RCP) to facilitate G-protein coupling to receptor/RAMP complexes using siRNA |
Collaborator Contribution | Dr Dickerson of Rochester has supplied us with his antibody directed against RCP |
Impact | None so far |
Start Year | 2016 |
Description | Royal Society Industrial Fellowship: Markov State Modelling |
Organisation | Heptares Therapeutics Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | Expertise in modelling GPCRs |
Collaborator Contribution | Access to specialist software; specialist knowledge on GPCRs and drug design |
Impact | Summer student trained in bioinformatics |
Start Year | 2017 |
Description | SMALPing of calcitonin receptor |
Organisation | Monash University |
Country | Australia |
Sector | Academic/University |
PI Contribution | We have supplied reagents and provided training for a research student to purify the calcitonin receptor using SMALPs |
Collaborator Contribution | Provision of a cell line expressing the calcitonin receptor and a student to do the experimental work |
Impact | Production of the purified calcitonin receptor for structural studies |
Start Year | 2015 |
Description | Article in community magazine describing recent research |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Some comments that the article was interesting I was subsequently invited to speak about my work, to a community group |
Year(s) Of Engagement Activity | 2015 |
Description | Article in community magazine on the importance of scientific evaluation |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | There were a few positive comments, but generally limited response Difficult to say! |
Year(s) Of Engagement Activity | 2015 |
Description | Drug Design Workshop for the giften and able |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | 8 Gifted and able students from Bromfords School, Essex, attended a week-long drug design workshop, which greatly increased the pupils enthusiasm for science. |
Year(s) Of Engagement Activity | 2016 |
Description | Magazine article |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | I have written an article for a community newsletter about my research work. |
Year(s) Of Engagement Activity | 2019 |
Description | Molecule of the Month |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Molecule of the month is a monthly, 1 page article that appears in a community magazine, "The Wheatland News", distributed to communities in south-east Shropshire. During the last year it has been mainly made available on-line. The article typically describes the function of a protein or drug molecule that is topical, either in the general news or the scientific literature. |
Year(s) Of Engagement Activity | 2021,2022,2023,2024 |
URL | https://media.acny.uk/media/venues/page/attachment/2021/11/Weatland_News_December_January_2021.pdf |
Description | Protein modelling master class |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Students from local schools visit the university and learn how to design drugs that bind to proteins using molecular modelling |
Year(s) Of Engagement Activity | 2016,2017 |
Description | Protein modelling masterclass |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Hands-on demonstration of protein modelling and its application in drug discovery to 6th formers |
Year(s) Of Engagement Activity | 2017 |
Description | Seminar at Department of Pharmacology, Cambridge |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Talk in front of researchers and undergraduate students of pharmacology at Cambridge |
Year(s) Of Engagement Activity | 2017 |
Description | Talk at village group |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Talk to around 15 people at group in the village of Highley about my work as scientist |
Year(s) Of Engagement Activity | 2017 |
Description | Talk at village group |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | I spoke about my work as a scientist to "Catalyst", a social group at Highley, close to where I live |
Year(s) Of Engagement Activity | 2016 |
Description | Talk to community group |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | There was a lot of discussion following the talk I was asked if a 6th former could spend a day in my lab, by a the friend of his parent, who attended the talk. This visit took place on 2-11-15 |
Year(s) Of Engagement Activity | 2015 |
Description | Talks for ELRIG at Lab Innovations exhibition, Birmingham |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Significant discussions after the talk Two new potential collaborations are being explored |
Year(s) Of Engagement Activity | 2015 |