Molecular dynamics analysis of mRNA capping: Characterising the activation mechanisms of the mammalian capping enzymes
Lead Research Organisation:
University of Dundee
Department Name: School of Life Sciences
Abstract
mRNA capping is vital for the regulation of genes in eukaryotic organisms. This capping is activated downstream of c-Myc, a major oncoprotein overexpressed in over 50% of human cancers, therefore, mRNA capping is a promising target for cancer therapeutics. The Capping Enzyme carries out the first two steps in this process. Many questions remain about its activation and regulation, limiting our ability to design drugs that target it. It is activated by binding to the phosphorylated C-terminal Domain of RNA Polymerase II. However, the molecular details of this activation mechanism have been elusive using conventional biochemical techniques.
I will address this problem from a new angle by using molecular dynamics simulations to study the conformational changes that occur upon C-terminal Domain binding. Further computational and biophysical analysis will be performed to characterise the interaction surface and catalytic core. An interdisciplinary collaboration with the Cowling lab will yield experimental evidence to support these findings.
Key Words and Skills:
Questions:
1. Explain interdisciplinary interface: Yes, it talks about collaboration between computational biophysics and experimental biology
2. Does project require significant amount of quantitative skills? YES
3. Does project require significant amount of whole organism physiology skills? NO
I will address this problem from a new angle by using molecular dynamics simulations to study the conformational changes that occur upon C-terminal Domain binding. Further computational and biophysical analysis will be performed to characterise the interaction surface and catalytic core. An interdisciplinary collaboration with the Cowling lab will yield experimental evidence to support these findings.
Key Words and Skills:
Questions:
1. Explain interdisciplinary interface: Yes, it talks about collaboration between computational biophysics and experimental biology
2. Does project require significant amount of quantitative skills? YES
3. Does project require significant amount of whole organism physiology skills? NO
People |
ORCID iD |
| Andrei Pisliakov (Primary Supervisor) |
Publications
Bage MG
(2021)
A novel RNA pol II CTD interaction site on the mRNA capping enzyme is essential for its allosteric activation.
in Nucleic acids research
Bueren-Calabuig JA
(2019)
Mechanism of allosteric activation of human mRNA cap methyltransferase (RNMT) by RAM: insights from accelerated molecular dynamics simulations.
in Nucleic acids research
Williamson G
(2020)
A two-lane mechanism for selective biological ammonium transport.
in eLife
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/N013735/1 | 04/09/2016 | 29/09/2025 | |||
| 1786154 | Studentship | MR/N013735/1 | 04/09/2016 | 30/05/2021 |
| Description | Academy of Medical Sciences Policy Internship Available to MRC-Funded PhD Students |
| Geographic Reach | National |
| Policy Influence Type | Contribution to a national consultation/review |
| Impact | I will be undertaking an internship at the Academy of Medical Sciences (AMS) in London starting in April 2019 and funded as part of my MRC PhD studentship. I will spend 3 months at the AMS central London offices as described on their internships page: https://acmedsci.ac.uk/about/administration/internship-schemes. During this time I will gain a fundamental understanding of the role of science policy and its impact on academic and commercial research. I will also have a unique opportunity to discuss the key issues that are affecting medical science today with the UK's most eminent medical scientists and health stakeholders. I will also provide the Academy with first-hand experience in Medical Scientific Research, making myself a useful member of the policy team. After the internship I will have built up key skills in communicating and disseminating scientific information. I will bring this experience back to the University of Dundee, using the skills gained in my ongoing doctoral research. |
| URL | https://acmedsci.ac.uk/about/administration/internship-schemes |
| Description | MRC Flexible Supplement Fund Award 2016/2017 (Conference Travel Grant) |
| Amount | £450 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 06/2017 |
| End | 07/2017 |
| Description | MRC Flexible Supplement Fund Award 2018/2019 (Awarded For AMS-MRC Policy Internship) |
| Amount | £5,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2019 |
| End | 07/2019 |
| Description | Cowling Lab Collaboration |
| Organisation | University of Dundee |
| Department | Centre for Gene Regulation and Expression |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | As part of my PhD, I am working closely within the lab of Professor Victoria Cowling at the University of Dundee. As part of this collaboration, I have performed computational simulations that have provided novel insights into the regulatory mechanism of the system being studied within the Cowling lab. I have disseminated these results to the Cowling lab and I have successfully undertaken experimental work within the Cowling lab to validate these results. I contribute to the collaboration by bringing a strong understanding of computational and structural biology. The results I am producing as part of this collaboration are enabling us to build up a more comprehensive understanding of the mechanisms of mRNA capping. |
| Collaborator Contribution | As part of the collaboration, I am undertaking experimental work within the Cowling lab. This requires a large number of resources, including equipment for protein purification and biochemical assays. As part of the collaboration, I am able to use the resources available in the Cowling lab. In addition, the Cowling lab produces internationally renowned research on the mRNA capping process. Therefore, the collaboration has allowed me to discuss my computational and experimental results with the leading experts in the field, ensuring that my own research is making a significant contribution. |
| Impact | The collaboration is ongoing as part of my PhD project, therefore these are listed in other sections. The collaboration has resulted in two publications in high-impact journals and is likely to result in additional publications in the future. The disciplines involved in this collaboration are: - Computational biology and chemistry - Biochemistry and cell biology |
| Start Year | 2017 |
| Description | Zachariae and Javelle Labs Collaboration |
| Organisation | University of Dundee |
| Department | Division of Computational Biology |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | As part of my PhD, I am working closely with the lab of Professor Ulrich Zachariae at the University of Dundee and Dr Arnoud Javelle at the Strathclyde Institute of Pharmacy and Biomedical Sciences. As part of this collaboration, I have performed computational simulations that have provided novel insights into the regulatory mechanism of ammonium transporters, a particular interest in the Zachariae and Javelle Labs. The results I produced as part of this collaboration enabled us to build up a more comprehensive understanding of the mechanisms of ammonium transporters. As part of this collaboration, I contributed to results and their presentation in a publication that was accepted in a high-impact journal. |
| Collaborator Contribution | I made a contribution to a considerably larger collaboration between the Zachariae and Javelle Labs, which included large-scale simulations and considerable experimental word. |
| Impact | The collaboration resulted in a paper accepted for publication in a high-impact journal. The disciplines involved in this collaboration are: - Computational biology and chemistry - Biochemistry and biophysics |
| Start Year | 2018 |
| Description | Zachariae and Javelle Labs Collaboration |
| Organisation | University of Strathclyde |
| Department | Strathclyde Institute of Pharmacy & Biomedical Sciences |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | As part of my PhD, I am working closely with the lab of Professor Ulrich Zachariae at the University of Dundee and Dr Arnoud Javelle at the Strathclyde Institute of Pharmacy and Biomedical Sciences. As part of this collaboration, I have performed computational simulations that have provided novel insights into the regulatory mechanism of ammonium transporters, a particular interest in the Zachariae and Javelle Labs. The results I produced as part of this collaboration enabled us to build up a more comprehensive understanding of the mechanisms of ammonium transporters. As part of this collaboration, I contributed to results and their presentation in a publication that was accepted in a high-impact journal. |
| Collaborator Contribution | I made a contribution to a considerably larger collaboration between the Zachariae and Javelle Labs, which included large-scale simulations and considerable experimental word. |
| Impact | The collaboration resulted in a paper accepted for publication in a high-impact journal. The disciplines involved in this collaboration are: - Computational biology and chemistry - Biochemistry and biophysics |
| Start Year | 2018 |
| Description | Teaching Python Programming to Undergraduate Physics Students at the University of Dundee |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Undergraduate students |
| Results and Impact | I worked as an assistant in tutorial workshops for a semester, teaching second-year Physics undergraduate students at the University of Dundee. The course was an introduction to Python and Matlab programming. I made substantial contributions to the tutorials, helping many of the students with any difficulties they had with the theory or implementation of the material they were learning. By the end of the semester the majority of the students had a strong grasp of programming. Over 80% of the class obtained an A or higher in this module, a notable increase from previous years. In addition, being a biologist teaching physics students, I introduced them to the relevance of using programming and physics in biological research. |
| Year(s) Of Engagement Activity | 2017 |