The quaternary structure of G protein-coupled receptors: implications for function and drug design

Lead Research Organisation: University of Glasgow
Department Name: School of Life Sciences

Abstract

Efforts to develop effective and novel small molecule medicines attract considerable interest from the public as well as from the scientific community. Medicines targeted at GPCRs are used very widely. Although the U.K. public are, in general, less well informed than their American counterparts, there is widespread recognition of the Product names of many of these medicines including a variety of anti-histaminergics and anti-hypertensive drugs. Dissemination of information produced from these studies will concentrate on traditional routes such as publication of articles in peer-reviewed Journals and the presentation of talks to informed audiences. I have published more than 350 articles and give some 15-20 lectures furth of Glasgow each year. However, I also plan to present public lectures related to my work to groups, including school children and junior undergraduate students to extend their knowledge base. The Glasgow Science centre and the outreach programmes of Glasgow University offer excellent opportunities to enhance public understanding of science. I have also previously been involved with presentations at the Edinburgh Science Festival and my position as a Fellow of the Royal Society of Edinburgh offers further opportunities as this is a central remit of the Society.

Technical Summary

G protein-coupled receptors (GPCRs) are the most tractable set of targets for the development of clinically effective, small molecule medicines. There is thus great interest in their structure, regulation and activation mechanisms. Data mining of genome sequencing programmes indicate that at least 380 genes in man encode GPCRs likely to be activated by endogenously produced regulators. It is becoming increasingly clear that GPCRs do not function as monomers but possess quaternary structure. Widespread co-expression of many GPCR gene products implies that individual GPCRs with significiant mutual affinity will have the potential to exist as hetero-dimers/oligomers as well a homo-dimers/oligomers. This programme of work will explore both the fundamental mechanisms that contribute to GPCR dimerisation and its selectivity and will study the details of hetero-dimeric interactions between pairs of GPCRs with physiologically relevant co-expression patterns where preliminary data indicates that their interactions alter function and/or pharmacology. Supported by grant G9811527 I developed the use of GPCR-G protein fusions. The GPCR-G protein fusion strategy offers an ideal means to examine the basis, selectivity and mechanisms of function of GPCR dimers. It also offers a highly novel means to monitor the function and potentially unique pharmacology only of hetero-dimers that form following expression of two different GPCRs. This approach will be supplemented by use of resonance energy transfer techniques and the ability of co-expressed fragments of GPCRs to reconstitute or to interfere with function. The programme of work will provide unique insights into the quaternary structure of the largest family of transmembrane signalling proteins and may have profound implications for the identification of novel therapeutic small molecules.

Publications

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Appelbe S (2009) Chapter 10. Hetero-oligomerization of chemokine receptors. in Methods in enzymology

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Ferré S (2009) Building a new conceptual framework for receptor heteromers. in Nature chemical biology

 
Description Member Nomenclature committee-International Union of Basic and Clinical Pharmacology
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
 
Description BBSRC Project Grant (Exploring the selectivity and consequences of GPCR homo and hetero- dimerisation/oligomerisation using RASSLs)
Amount £416,349 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States of America
Start 01/2008 
End 04/2010
 
Description BBSRC Project Grant (The molecular basis of cannabinoid CB1 receptor regulation of the sensitivity of orexin-1 receptor signalling)
Amount £197,433 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 08/2008 
End 10/2011
 
Description MRC Programme Grant
Amount £1,784,830 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2009 
End 09/2014
 
Description Servier Laboratories Ltd., Research Contract
Amount £254,635 (GBP)
Organisation Servier Laboratories 
Sector Private
Country France, French Republic
Start 04/2008 
End 06/2012
 
Title Flp-In cell lines 
Description Cell lines that stably express or can be induced to express G protein-coupled receptors linked to a suitable reporter gene, this may be a fluorescent polypeptide, e.g. GFP or a enzyme e.g. luciferase. 
Type Of Material Cell line 
Year Produced 2007 
Provided To Others? Yes  
Impact Such reagents/cells lines are used widely in academic research, and in drug screening. 
 
Title GPCR-G protein fusions 
Description Links a G protein-coupled receptor to a G protein to produce a single open reasding frame incorporating both functionalities 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact Used in drug screening and a variation of this resulted in the submission of a patent that has bene licensed by two pharmaceutical companies 
 
Title GPCR-OKB: 
Description The G Protein Coupled Receptor Oligomer Knowledge Base. 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2009 
Provided To Others? Yes  
Impact This is dificult to assess. Rapid expansion of available data about G Protein Coupled Receptor (GPCR) dimers/oligomers over the past few years requires an effective system to organize this information electronically. Based on an ontology derived from a community dialogue involving colleagues using experimental and computational methodologies, we developed the GPCR-Oligomerization Knowledge Base (GPCR-OKB). GPCR-OKB is a system that supports browsing and searching for GPCR oligomer data. Such data were manually derived from the literature. While focused on GPCR oligomers, GPCR-OKB is seamlessly connected to GPCRDB, facilitating the correlation of information about GPCR protomers and oligomers. Availability and Implementation: The GPCR-OKB web application is freely available at http://www.gpcr-okb.org 
URL http://www.gpcr-okb.org
 
Description Dopamine D2/ dopamine D3 receptor interactions 
Organisation Servier Laboratories
Country France, French Republic 
Sector Private 
PI Contribution Efforts to explore the potential for novel targets for therapeutic drugs. Funding, and access to non commercially available receptor ligands
Collaborator Contribution Contract research
Impact No publications have yet emerged from this work
Start Year 2007
 
Description Glaxo SmithKline Studentship Free Fatty Acid receptors 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution I was PI for the CASE studentship
Impact This is NOT directly related to the work in the programme but the work performed in the programme resulted in interest in the potential for novel aspects of drug discovery that was supported by a studentship from GSK. This has expanded our efforts in the general area of G-protein-coupled receptor dimerisation.
Start Year 2007
 
Description screening for heterodimer selective ligands. Relevance to pain and inflammation 
Organisation Cara Therapeutics
Country United States of America 
Sector Private 
PI Contribution This is NOT directly related to the work in the programme but the work performed in the programme resulted in interest in the potential for novel aspects of drug discovery that was supported by a research contract from Cara Therapeutics. This has expanded our efforts in the general area of G-protein-coupled receptor dimerisation and the concept that receptor hetero-dimers may be novel targets for therapeutic drugs.
Collaborator Contribution Efforts to explore the potential for novel targets for therapeutic drugs. Funding, and access to non-commercially available receptor ligands
Impact This is NOT directly related to the work in the programme but the work performed in the programme resulted in interest in the potential for novel aspects of drug discovery that was supported by a research contract from Cara Therapeutics. This has expanded our efforts in the general area of G-protein-coupled receptor dimerisation and the concept that receptor hetero-dimers may be novel targets for therapeutic drugs.
Start Year 2007
 
Title Dimer-Screen Technology 
Description This is a technology application deriving from both MRC and BBSRC funding to allow the development of a screening platform fo the identification of ligands with affinity and seelctivity for GPCR heteromers. 
IP Reference US2008286828 
Protection Patent granted
Year Protection Granted 2008
Licensed Yes
Impact The technology remains an integral part of the basic research portfolio of my team
 
Company Name Cara Therapeutics 
Description The compnay seeks novel tratments in the areas of pain and inflammation. Currently the most advanced programme is in 'phase II' clinical trials. http://www.caratherapeutics.com/ 
Year Established 2007 
Impact Until the clinical trials are complete the impact cannot be assessed.
Website http://www.caratherapeutics.com/
 
Description Lecture to Industry meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Approx 200 researchers predominantly from the Pharma/Biotech sector attend annually a series of meetimngs at the interface of industrial and academic research in this area.

I was subsequently invited to discuss issues and topics arising by a number of Pharma companies
Year(s) Of Engagement Activity 2009,2010,2011,2012,2013
 
Description Talks at International meetings 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact I give a large number of seminars at conferences, at University departments and to Pharmaceutical/biotechnology companies. One I have listed the date above for was 'Novel Assay Technologies for the Discovery of GPCR Drugs", Screening Europe Conference, Barcelona, Spain. Keynote Presentation

In in the perio 2008-2013 I have given more than 50 such presentations

Press conference
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010