Arthur Christopoulos
Arthur Christopoulos is an Australian Professor of Analytical Pharmacology at Monash University. He is the recipient of numerous national and international awards, including the 2013 John J. Abel Award from the American Society for Pharmacology and Experimental Therapeutics and the Rand Medal from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, the 2014 IUPHAR Analytical Pharmacology Lecturer, a 2015 Doctor of Laws from the National and Kapodistrian University of Athens, Greece, the 2016 recipient of the Gaddum Memorial Award from the British Pharmacological Society and the 2016 GSK Award for Research Excellence. Since 2014, Clarivate Analytics have annually named him a Highly Cited Researcher in Pharmacology and Toxicology. In 2017 he was elected a Fellow of the Australian Academy of Health and Medical Sciences and in 2018 he was elected as a Councillor of the International Union of Basic and Clinical Pharmacology and a Fellow of the British Pharmacological Society. In 2019 he was appointed Dean of Monash University’s Faculty of Pharmacy and Pharmaceutical Sciences.
Early life
Christopoulos obtained a Bachelor of Pharmacy and his PhD from the Victorian College of Pharmacy, Monash University, and subsequently pursued postdoctoral studies in the Department of Neuroscience Research in Psychiatry, University of Minnesota, prior to returning to Australia to establish his laboratory within the Department of Pharmacology, University of Melbourne. In 2006, he moved to Monash University and holds joint appointments in the Faculty of Pharmacy and Pharmaceutical Sciences and Faculty of Medicine.Career
Arthur Christopoulos’ research focuses on allosteric mechanisms of drug action and signal-pathway ‘biased’ agonism at G protein-coupled receptors – the largest class of drug targets - and incorporates molecular pharmacology, computational and mathematical modeling, medicinal chemistry, structural and chemical biology, and animal models of behavior. He has served on the Editorial Board of several scientific journals, including Molecular Pharmacology, the Journal of Pharmacology and Experimental Therapeutics, Pharmacological Reviews, ACS Chemical Neuroscience, the British Journal of Pharmacology and ACS Pharmacology and Translational Sciences. Prior to taking up his current position as Dean, Professor Christopoulos held a Senior Principal Research Fellowship of the National Health and Medical Research Council of Australia.Selected Works
- Draper-Joyce, C.J., Khosouei, M., Thal. D.M., Liang, Y.L., Nguyen, A.T.N., Gurness, S.G.B., Venugopal, H., Baltos, J., Plitzko, J.P., Danev, R., Baumeisterm W., May, L.T., Wootten, D., Sexton, P.M., Glukhova, A. and A. Christopoulos Structure of the adenosine-bound human A1 receptor-Gi complex. Nature 558: 559-563.
- Harvey Motulsky, Arthur Christopoulos. Fitting Models to Biological Data Using Linear and Nonlinear Regression: A practical guide to curve fitting. Oxford University Press. 2004.
- Liang, Y.L., Khoshouei, M., Deganuti, G., Glukhova, A., Koole, C., Peat, T.S., Radjainia, M., Plitzko, J.M., Baumeister, W., Miller, L.M., Hay, D.L., Christopoulos, A., Reynolds, C.A., Wootten, D. and P M. Sexton Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor. Nature 561: 492-497.
- Thal, D.M., Glukhova, A., Sexton P.M. and A. Christopoulos Structural insights into G-protein-coupled receptor allostery. Nature 559: 45-53.
- Berizzi, A., Perry, C., Shackleford, D., Lindsley, C., Jones, C., Chen, N., Sexton, P.M., Christopoulos, A., Langmead, C.J. and A.J. Lawrence Muscarinic M5 receptors modulate ethanol seeking in rats. Neuropsychopharmacol., 43: 1510-1517.
- Wootten, D., Christopoulos, A., Solano, M.M., Babu, M.M., and P.M. Sexton Mechanisms of signalling and bias in G-protein coupled receptors. Nat. Rev. Mol. Cell Biol. 19: 638-653.
- Korczynska, M., Clark, M.J., Valant, C., Moo, E.V., Abold, S., Weiss, D.R., Torosyan, H., Huang, W., Kruse, A.C., May, L.T., Baltos, J., Sexton, P.M., Kobilka, B.K., Christopoulos, A., Shoichet, B.K., and R.K. Sunahara Structure-based discovery of selective positive allosteric modulators of antagonists for the M2 muscarinic acetylcholine receptor. Proc. Nat. Acad. Sci. 115: E2419-E2428.
- Liang, Y.-L., Khosouei, M., Glukhova, A., Furness, S.G.B., Clydesdale, L., Koole, C., Troung, T.T., Thal, D.M., Lei, S., Radjainia, M., Danev, R., Baumeister, W., Wang, M.-W., Christopoulos, A., Sexton, P.M. and D. Wootten Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex. Nature 555: 121-125.
- Liang, Y.L., Khoshouei, M., Radjainia, M., Zhang, Y., Glukhova, A., Tarrasch, J., Thal, D.M., Furness, S.G.B., Christopoulos, G., Coudrat, T., Danev, R., Baumeister, W., Miller, LJ., Christopoulos, A., Kobilka, B.K., Wootten, D., Skiniotis, G. and P.M. Sexton Phase-plate cryo-EM structure of a class B GPCR-G protein complex. Nature 546: 118-123.
- Glukhova, A., Thal, D.T., Nguyen, A.T.N., Vecchio, E.A., Jörg, M., Scammells, P.J., May, L.T., Sexton, P.M. and A. Christopoulos Structure of the adenosine A1 receptor reveals the basis for subtype selectivity. Cell 168: 867-877.
- Bradley, S.J., Bourgognon, J.-M., Sanger, H.E., Verity, N., Mogg, A., White, D.J., Butcher, A.J., Moreno, J.A., Molloy, C., Macedo-Hatch, T., Edwards, J.E., Wess, J., Pawlak, R., Read, D.J., Sexton, P.M., Broad, L.M., Steinert, J.R., Mallucci, G.R., Christopoulos, A., Felder, C.C. and A.B. Tobin M1-muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss. J. Clin. Invest. 127: 487-499.
- Lane, J.R., May, L.T., Parton, R.G., Sexton, P.M and A. Christopoulos A kinetic view of GPCR allostery and biased agonism. Nature Chem. Biol. 13: 929-937.
- Qin, R.C.X., May, L.T., Li, R., Cao, N., Rosli, S., Deo, M., Alexander, A.E., Horlock, D., Bourke, J.E., Yang, Y.H., Stewart, A.G., Kaye, D.M., Du, X.-J., Sexton, P.M., Christopoulos, A., Gao X.-M. and R. H. Ritchie Small-molecule biased formyl peptide receptor agonist Compound-17b protects against myocardial ischemia-reperfusion injury in mice. Nature Comm. 8: 14232.
- Furness, S.G.B., Liang, Y.-L., Nowell, C.J., Halls, M.L., Wookey, P.J., Dal Maso, E., Inoue, A., Christopoulos, A., Wootten, D. and P.M. Sexton Ligand-dependent modulation of G protein conformation alters drug efficacy. Cell. 167: 739-749.
- Miao, Y., Goldfeld, D., Moo, E.V., Sexton, P.M., Christopoulos, A., McCammon, A.J. and C. Valant Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor. Proc. Nat. Acad. Sci. . 113: E5675-E5684.
- Wootten, D., Reynolds, C.A., Smith, K.J., Mobarec, J.C., Koole, C., Savage, E., Pabreja, K., Simms, J., Sridhar, R., Furness, S.G.B., Liu, M., Thompson, P.E., Miller, L.J., Christopoulos, A. and P.M. Sexton The GLP-1 receptor extracellular surface is a molecular trigger for biased agonism. Cell. 165: 1632-1643.
- Leach, K., Gregory, K.J., Kufareva, I., Khajehali, E., Cook, A.E., Abagyan, R., Conigrave, A.D., Sexton P.M. and A. Christopoulos Towards a structural understanding of allosteric drugs at the human calcium sensing receptor Cell Res. 26: 574-592.
- Klein Herenbrink, C., Sykes, D.A., Donthamsetti, P., Canals, M., Coudrat, T., Shonberg, J., Scammells, P.J., Capuano, B., Sexton, P.M., Charlton, S.J., Javitch, J.A., Christopoulos, A. and J.R. Lane The role of kinetic context in apparent biased agonism at GPCRs. Nature Comm. 7: 10842
- Thal, D.M., Sun, B., Feng, D., Nawaratne, V., Leach, K., Felder, C.C., Bures, M.G., Evans, D.A., Weis, W.I., Bachhawat, P., Kobilka, T.S., Sexton, P.M., Kobilka, B.M. and A. Christopoulos Crystal structures of the M1 and M4 muscarinic acetylcholine receptors and insights into their allosteric modulation. Nature. 531: 335–340.
- Lane, J.R., Donthamsetti, P., Shonberg, J., Draper-Joyce, C.J., Dentry, S., Michino, M., Shi, L., López, L., Scammells, P.J., Capuano, B., Sexton, P.M., Javitch, J.A. and A. Christopoulos A new mechanism of allostery in a G protein-coupled receptor dimer. Nature Chem. Biol. 10: 745-752.
- Christopoulos, A., Changeux, J.P., Catterall, W.A., Fabbro, D., Burris, T.P., Cidlowski, J.A., Olsen, R.W., Peters, J.A., Neubig, R.R., Pin, J.P., Sexton, P.M., Kenakin, T.P., Ehlert, F.J., Spedding M. and C.J. Langmead International Union of Basic and Clinical Pharmacology. XC. Multi-site Pharmacology: Recommendations for the nomenclature of receptor allosterism and allosteric ligands. Pharmacol. Rev. 66: 918-947.
- Valant, C., May, L.T., Aurelio, L., Chuo, C.H., White, P.J., Baltos, J., Sexton, P.M., Scammells, P.J. and A. Christopoulos Separation of on-target efficacy from adverse effects through rational design of a bitopic adenosine receptor agonist. Proc. Nat. Acad. Sci. 111: 4614-4619.
- Kruse, A.C., Kobilka, B.K., Gautam, D., Sexton, P.M., Christopoulos, A. and J., Wess Insights into muscarinic acetylcholine receptor biology, pharmacology, and structure. Nature Rev. Drug Discovery, 13: 549-560.
- Dror, R.O., Green, H.F., Valant, C., Borhani, D.W., Valcourt, J.R., Pan, A.C., Arlow, D.H., Canals, M., Lane, J.R., Rahmani, R., Baell, J.B., Sexton, P.M., Christopoulos, A. and D.E. Shaw Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs. Nature. 503: 295-299
- Kruse, A.C., Ring, A.M., Manglik, A., Hu, J., Hu, K., Eitel, K., Hübner, H., Pardon, E., Valant, C., Sexton, P.M., Christopoulos, A., Felder, C.C., Gmeiner, P., Steyert, J., Weiss, W.I., Garcia, K.C., Wess, J. and B.K. Kobilka Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature. 504: 101-106.
- Mistry, S., Valant, C., Sexton, P., Capuano, B., Christopoulos, A. and P.J. Scammells Synthesis and pharmacological profiling of analogues of BQCA as allosteric modulators of the M1 muscarinic receptor. J. Med. Chem. 56: 5151-5172.
- Leach, K., Wen, A., Cook, A.E., Sexton, P.M., Conigrave, A.D, and A. Christopoulos Impact of clinically relevant mutations on the pharmacoregulation and signaling bias of the calcium sensing receptor by positive and negative allosteric modulators. Endocrinology 154: 1105-1116.
- Gregory, K.J., Sexton, P.M., Tobin, A.B. and A. Christopoulos Stimulus bias provides evidence for conformational constraints in the structure of a G protein-coupled receptor. J. Biol. Chem. 287: 37066-37077.
- Kenakin, T., Watson, C., Muniz-Medina, V. and A. Christopoulos A simple method to quantify functional selectivity and agonist bias. ACS Chem. Neurosci. 3: 193-203
- Wootten D., Savage E.E., Valant C., May L.T., Sloop K.W., Ficorilli J., Showalter A.D., Willard F.S., Christopoulos A. and P.M. Sexton. Allosteric modulation of endogenous metabolites as an avenue for drug discovery. Mol Pharmacol., 2012, 82:281-90.
- Valant, C., Felder, C.C., Sexton, P.M. and A. Christopoulos Probe-dependence in the allosteric modulation of a G protein-coupled receptor: Implications for detection and validation of allosteric ligand effects. Mol. Pharmacol. 81: 41-52.
- Canals, M., Lane, J.R., Wen, A., Scammells, P.J., Sexton, P.M. and A. Christopoulos A Monod-Wyman-Changeux mechanism can explain G protein-coupled receptor allosteric modulation. J. Biol. Chem. 287: 650-659.
- Valant, C., Gregory, K.J., Hall, N.E., Scammells, P.J., Lew, M.J., Sexton, P.M. and A. Christopoulos A novel mechanism of G protein-coupled receptor functional selectivity: muscarinic partial agonist McN-A-343 as a bitopic orthosteric/allosteric ligand, J. Biol. Chem, 283: 29312-29321.
- Motulsky, H. and Christopoulos, A. Fitting Models to Biological Data Using Linear and Nonlinear Regression: A practical guide to curve fitting. Oxford University Press. 2004.
- Christopoulos, A. and T. Kenakin G protein-coupled receptor allosterism and complexing, Pharmacol. Rev. 54: 323-374.
- Christopoulos, A. Allosteric binding sites on cell-surface receptors: Novel targets for drug discovery. Nature Rev. Drug Discovery 1: 198-210.