Data Science approaches to GPCR signaling and implications for drug discovery

Madan Babu (St Jude Children’s Research Hospital, TN, USA)

09 June 2025

Seminar

Pratical info

17:00 - 18:00

Conference room Rosalind Franklin

research professional

Reduced mobility access

G protein-coupled receptors (GPCRs) participate in diverse physiological processes, ranging from sensory responses such as vision, taste, and smell to those regulating behavior, the immune and the cardiac system among others. The ~800 human GPCRs sense diverse signaling molecules such as hormones and neurotransmitters to allosterically activate the associated G proteins, which in turn regulate diverse intracellular signaling pathways. In this manner, GPCRs regulate virtually every aspect of human physiology. Not surprisingly, GPCRs are the targets of over one-third of all prescribed human drugs. Our group develops data science approaches to investigate GPCR signaling at multiple levels of complexity, from the atomic-scale to tissue and population-scale.
In this presentation, I will first discuss how one can leverage pharmacology and structural data to understand the origins of efficacy and potency. I will then focus on the chemokine-GPCR signaling system that governs cell movement to describe the molecular determinants of selectivity and promiscuity in this ligand-receptor system. Specifically, I will discuss how such insights can be used to design chemokine ligands for possible cell therapy applications. Finally, I will present ongoing work that utilize gene expression data during different stages of development to uncover principles of developmental dynamics of GPCRs. I will discuss the implications of the findings for drug development for the fetal, pediatric, pregnant and geriatric population. I will conclude by highlighting how studying GPCR signaling at all these scales can provide a rich source of new hypotheses with implications for personalized medicine, drug development and understanding basic receptor biology.

Madan Babu is invited by Ralf Jockers.

Biosketch

M. Madan Babu is the George J Pedersen Endowed Chair of Biological Data Science in the Department of Structural Biology at St Jude Children’s Research Hospital. He is also the Director of the Center of Excellence for Data Driven Discovery and the Senior Vice President for Data Science at St Jude. Before joining St Jude, Madan was a Programme Leader at the MRC Laboratory of Molecular Biology in Cambridge, UK (2006-2020). Madan’s research group develops data science approaches to make biological discoveries with a particular emphasis on understanding how the precise structure and intrinsically disordered regions of proteins such as GPCRs contribute to cellular function. His interests and publications span diverse areas in life sciences relevant to human diseases and medicine.

The work from his group has been recognized with national and international awards including the Royal Society’s Francis Crick Medal, the Blavatnik Award for his work elucidating the functions of key proteins in the human genome, and the EMBO Gold Medal for his fundamental contributions to the field of computational molecular biology; specifically for his discoveries in the areas of GPCR signaling and intrinsically disordered proteins. Madan is the Chief Editor of Molecular Systems Biology and an Executive Editor of Nucleic Acids Research. He is an elected member of EMBO, Fellow of UK Academy of Medical Science, and the Royal Society of London. Madan did his post-doc from the NCBI, NIH (2006), received his Ph.D. from the MRC Lab of Molecular Biology and Trinity College, Cambridge, UK (2004) and his undergraduate degree from the Centre for Biotechnology at Anna University in India (2001).

Selected publications

A. Kleist, A. B.*, Szpakowska, M., Talbot, L. J., Slodkowicz, G., Malinverni, D., Thomas, M. A., Crawford, K., S., McGrail, D. J., Dishman, A. F., Wedemeyer, M. J., Sluter, M., Yi, S. S., Sahni, N., Peterson, F. C., Chevign., A., Volkman, B. F.* & Babu, M. M.* Encoding and decoding selectivity and promiscuity in the human chemokine-GPCR interaction network. Cell, (2025). doi: 10.1016/j.cell.2025.03.046. PMID: 40273912
B. Heydenreich, F. M., Marti-Solano, M., Sandhu, M., Kobilka, B. K., Bouvier, M. & Babu, M. M.* Molecular determinants of ligand efficacy and potency in GPCR signaling. Science 382, eadh1859, (2023). doi: 10.1126/science.adh1859. PMID: 38127743.
C. Flock T*, Hauser AS, Lund N, Gloriam DE, Balaji S, Babu M.M.* (2017). Selectivity determinants of GPCR-G-protein binding. Nature, 545(7654):317-322. doi: 10.1038/nature22070. PMID: 28489817
D. Venkatakrishnan AJ*, Deupi X, Lebon G, Heydenreich FM, Flock T, Miljus T, Balaji S, Bouvier M, Veprintsev DB, Tate CG, Schertler GF, Babu M.M.*(2016). Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region. Nature, 536(7617):484-7. doi: 10.1038/nature19107. PMID: 27525504
E. Flock T*, Ravarani CNJ, Sun D, Venkatakrishnan AJ, Kayikci M, Tate CG, Veprintsev DB, Babu M.M.* (2015). Universal allosteric mechanism for Gα activation by GPCRs. Nature, 524(7564):173-179. doi: 10.1038/nature14663. PMID: 26147082 F. Venkatakrishnan AJ*, Deupi X, Lebon G, Tate CG, Schertler GF, Babu M.M.* (2013). Molecular signatures of G-protein-coupled receptors. Nature, 494(7436):185-94. doi: 10.1038/nature11896. PMID: 23407534
G. Hauser AS*, Chavali S, Masuho I, Jahn LJ, Martemyanov KA, Gloriam DE, Babu M.M.* (2018). Pharmacogenomics of GPCR Drug Targets. Cell, 172(1-2):41-54. doi: 10.1016/j.cell.2017.11.033. PubMed PMID: 29249361
H. Marti-Solano, M.*, Crilly, S. E., Malinverni, D., Munk, C., Harris, M., Pearce, A., Quon, T., Mackenzie, A. E., Wang, X., Peng, J., Tobin, A. B., Ladds, G., Milligan, G., Gloriam, D. E., Puthenveedu, M. A. & Babu, M. M.* (2020). Combinatorial expression of GPCR isoforms affects signalling and drug responses. Nature, 587, 650-656. doi: 10.1038/s41586-020-2888-2. PMID: 33149304.

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