Professor Patrick Sexton
NHMRC Senior Principal Research Fellow, Professor of Pharmacology, Drug Discovery Biology theme, Monash Institute of Pharmaceutical Sciences, Monash University
G protein-coupled receptors (GPCRs) are the largest family of cell surface drug targets. Consequently, there is high interest in understanding the structure of members of this receptor superfamily and molecular detail of how ligands and transducer proteins interact with the receptors. While x-ray crystallography has been the mainstay for GPCR structure determination, this method requires modification of receptors to limit flexibility and to enable crystal packing, and has been refractory to capturing fully active, transducer (G protein) complexed receptor structure. Our laboratory has been applying single particle cryo-EM to determination of active GPCR structures, using minimally modified receptors. We have now solved >20 structures of 11 unique receptors, most at resolutions at or below 3 A and are gaining insights into diverse modes of ligand binding and G protein coupling. An imbalance of hepatocyte PAI1 and tPA contributes to decreased systemic fibrinolysis in obesity. However, the fibrinolysis defect in obesity is limited by a novel compensatory pathway in which PAI1, increases tPA mRNA. Therapeutic boosting of this compensatory pathway, inhibition of the DACH1-tPA repression pathway, and/or inhibition of hepatocyte PAI1 expression may provide novel means to restore fibrinolytic balance in obesity.
Professor Sexton is a NHMRC Senior Principal Research Fellow at the Monash Institute of Pharmaceutical Sciences. He is a leader in the study of GPCRs, biased agonism, on allosteric interactions between GPCRs and other proteins, and small molecule ligands. Prof. Sexton’s awards include the ASCEPT Lecturer award, Endocrine Society of Australia Senior Plenary award, Rand Medal (ASCEPT), Vane Medal (British Pharmacological Society (BPS)), and the GSK Research Excellence award. Prof. Sexton is a Clarivate Analytics Highly Cited Researcher, an adjunct Professor of Fudan University, a SAB member for the Chinese National Centre for Drug Screening, an elected Fellow of the BPS and Editor-in-Chief for ACS Pharmacology and Translational Science.
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