About the Project
G protein-coupled receptors (GPCRs), encoded by over 800 individual genes in humans, are the largest family of membrane proteins6. They are widely expressed in different tissues and are ubiquitous in the control of physiological processes6. Given the importance of GPCRs in development and physiology, it is not surprising that perturbations in GPCRs and/or their transducers drives the initiation and progression of disease. Currently GPCRs comprise ~30% of all drug targets, but these drugs act at only a small subset of the GPCR repertoire and there is intense interest in further pharmaceutical exploitation of these proteins6,10.
A key component of GPCRs is the breadth of transducer proteins that they can engage. These not only include heterotrimeric G proteins, the canonical transducer class, but also regulatory and scaffolding proteins such as arrestins and AKAPs that initiate or control distinct patterns of signalling6,10. In humans, there are 16Gα, 5Gβ and 13Gγ subunits that can combine to form heterotrimeric G proteins. Each α subunit can signal independently, whereas the βγ subunits are obligate heterodimers that function as a single unit. While early research focussed on signalling mediated by the α-subunit, it is now acknowledged that signalling and regulatory functions are also derived via the βγ-subunits, including scaffolding of receptor kinases, and modulation of ion channel activity10.
A major objective of the group is to understand how GPCR signalling is mediated by different transducer proteins1-10. This project will involve the use of comparative genomics, sequence and structural analysis, network analysis, gene expression analysis as well as population genomics and cancer genomics data analysis to investigate the following questions:
(1) What is the molecular mechanism of Gβγ activation?
(2) What are the selectivity determinants of the Gα, Gβ and Gγ subunits that govern the formation of the heterotrimeric G protein complexes in human health and disease?
References
1. Selectivity determinants of GPCR-G-protein binding.
Flock T, Hauser AS, Lund N, Gloriam DE, Balaji S, Babu MM.
Nature. 2017 May 18;545(7654):317-322. doi: 10.1038/nature22070.
2. Universal allosteric mechanism for Gα activation by GPCRs.
Flock T, Ravarani CNJ, Sun D, Venkatakrishnan AJ, Kayikci M, Tate CG, Veprintsev DB, Babu MM.
Nature. 2015 Aug 13;524(7564):173-179. doi: 10.1038/nature14663.
3. Visualization and analysis of non-covalent contacts using the Protein Contacts Atlas.
Kayikci M, Venkatakrishnan AJ, Scott-Brown J, Ravarani CNJ, Flock T, Babu MM.
Nat Struct Mol Biol. 2018 Feb;25(2):185-194. doi: 10.1038/s41594-017-0019-z.
4. Pharmacogenomics of GPCR Drug Targets.
Hauser AS, Chavali S, Masuho I, Jahn LJ, Martemyanov KA, Gloriam DE, Babu MM.
Cell. 2018 Jan 11;172(1-2):41-54.e19. doi: 10.1016/j.cell.2017.11.033.
5. Probing Gαi1 protein activation at single-amino acid resolution.
Sun D, Flock T, Deupi X, Maeda S, Matkovic M, Mendieta S, Mayer D, Dawson R, Schertler GFX, Babu MM, Veprintsev DB.
Nat Struct Mol Biol. 2015 Sep;22(9):686-694. doi: 10.1038/nsmb.3070.
6. Molecular signatures of G-protein-coupled receptors.
Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GF, Babu MM.
Nature. 2013 Feb 14;494(7436):185-94. doi: 10.1038/nature11896
7. Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region.
Venkatakrishnan AJ, Deupi X, Lebon G, Heydenreich FM, Flock T, Miljus T, Balaji S, Bouvier M, Veprintsev DB, Tate CG, Schertler GF, Babu MM.
Nature. 2016 Aug 25;536(7617):484-7.
8. Molecular mechanism of modulating arrestin conformation by GPCR phosphorylation.
Sente A, Peer R, Srivastava A, Baidya M, Lesk AM, Balaji S, Shukla AK, Babu MM, Flock T.
Nat Struct Mol Biol. 2018 Jun;25(6):538-545. doi: 10.1038/s41594-018-0071-3.
9. Structured and disordered facets of the GPCR fold.
Venkatakrishnan AJ, Flock T, Prado DE, Oates ME, Gough J, Babu MM.
Curr Opin Struct Biol. 2014 Aug;27:129-37. doi: 10.1016/j.sbi.2014.08.002.
10. Mechanisms of signalling and biased agonism in G protein-coupled receptors
Wootten D, Christopoulos A, Marti-Solano M, Babu MM, Sexton PM
Nature Reviews Molecular Cell Biology. doi: 10.1038/ s41580-018-0049-3
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