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Patrick Michael Sexton

Education

Ph.D., Department of Medicine, Austin Hospital. University of Melbourne, 1988

Current position

Professor of Pharmacology, Monash University
NHMRC Principal Research Fellow
Theme Leader, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences

Publications (since 2010)

  1. Mistry, S. N., Valant, C., Sexton, P. M., Capuano, B., Christopoulos, A. and Scammells, P. J. (2013). Synthesis and Pharmacological Profiling of Analogues of Benzyl Quinolone Carboxylic Acid (BQCA) as Allosteric Modulators of the M1 Muscarinic Receptor. J Med Chem 56(12): 5151-5172.
  2. Savage, E. E., Wootten, D., Christopoulos, A., Sexton, P. M. and Furness, S. G. (2013). A simple method to generate stable cell lines for the analysis of transient protein-protein interactions. Biotechniques 54(4): 217-221.
  3. Wootten, D., Simms, J., Miller, L. J., Christopoulos, A. and Sexton, P. M. (2013). Polar transmembrane interactions drive formation of ligand-specific and signal pathway-biased family B G protein-coupled receptor conformations. Proc Natl Acad Sci U S A 110(13): 5211-5216.
  4. Wootten, D., Savage, E. E., Willard, F. S., Bueno, A. B., Sloop, K. W., Christopoulos, A. and Sexton, P. M. (2013). Differential activation and modulation of the glucagon-like peptide-1 receptor by small molecule ligands. Mol Pharmacol 83(4): 822-834.
  5. Abdul-Ridha, A., Lane, J. R., Sexton, P. M., Canals, M. and Christopoulos, A. (2013). Allosteric modulation of a chemogenetically modified G protein-coupled receptor. Mol Pharmacol 83(2): 521-530.
  6. Leach, K., Wen, A., Davey, A. E., Sexton, P. M., Conigrave, A. D. and Christopoulos, A. (2012). Identification of molecular phenotypes and biased signaling induced by naturally occurring mutations of the human calcium-sensing receptor. Endocrinology 153(9): 4304-4316.
  7. Harikumar, K. G., Wootten, D., Pinon, D. I., Koole, C., Ball, A. M., Furness, S. G., Graham, B., Dong, M., Christopoulos, A., Miller, L. J. and Sexton, P. M. (2012). Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery. Proc Natl Acad Sci U S A 109(45): 18607-18612.
  8. Gregory, K. J., Sexton, P. M., Tobin, A. B. and Christopoulos, A. (2012). Stimulus bias provides evidence for conformational constraints in the structure of a G protein-coupled receptor. J Biol Chem 287(44): 37066-37077.
  9. Dong, M., Xu, X., Ball, A. M., Makhoul, J. A., Lam, P. C., Pinon, D. I., Orry, A., Sexton, P. M., Abagyan, R. and Miller, L. J. (2012). Mapping spatial approximations between the amino terminus of secretin and each of the extracellular loops of its receptor using cysteine trapping. FASEB J 26(12): 5092-5105.
  10. Willard, F. S., Wootten, D., Showalter, A. D., Savage, E. E., Ficorilli, J., Farb, T. B., Bokvist, K., Alsina-Fernandez, J., Furness, S. G., Christopoulos, A., Sexton, P. M. and Sloop, K. W. (2012). Small molecule allosteric modulation of the glucagon-like Peptide-1 receptor enhances the insulinotropic effect of oxyntomodulin. Mol Pharmacol 82(6): 1066-1073.
  11. Leach, K., Wen, A., Davey, A. E., Sexton, P. M., Conigrave, A. D. and Christopoulos, A. (2012). Identification of molecular phenotypes and biased signaling induced by naturally occurring mutations of the human calcium-sensing receptor. Endocrinology 153(9): 4304-4316.
  12. Wootten, D., Savage, E. E., Valant, C., May, L. T., Sloop, K. W., Ficorilli, J., Showalter, A. D., Willard, F. S., Christopoulos, A. and Sexton, P. M. (2012). Allosteric modulation of endogenous metabolites as an avenue for drug discovery. Mol Pharmacol 82(2): 281-290.
  13. Cawston, E. E., Lam, P. C., Harikumar, K. G., Dong, M., Ball, A. M., Augustine, M. L., Akgun, E., Portoghese, P. S., Orry, A., Abagyan, R., Sexton, P. M. and Miller, L. J. (2012). Molecular basis for binding and subtype selectivity of 1,4-benzodiazepine antagonist ligands of the cholecystokinin receptor. J Biol Chem 287(22): 18618-18635.
  14. Valant, C., Aurelio, L., Devine, S. M., Ashton, T. D., White, J. M., Sexton, P. M., Christopoulos, A. and Scammells, P. J. (2012). Synthesis and characterization of novel 2-amino-3-benzoylthiophene derivatives as biased allosteric agonists and modulators of the adenosine A(1) receptor. J Med Chem 55(5): 2367-2375.
  15. Koole, C., Wootten, D., Simms, J., Savage, E. E., Miller, L. J., Christopoulos, A. and Sexton, P. M. (2012). Second extracellular loop of human glucagon-like peptide-1 receptor (GLP-1R) differentially regulates orthosteric but not allosteric agonist binding and function. J Biol Chem 287(6): 3659-3673.
  16. Koole, C., Wootten, D., Simms, J., Miller, L. J., Christopoulos, A. and Sexton, P. M. (2012). Second extracellular loop of human glucagon-like peptide-1 receptor (GLP-1R) has a critical role in GLP-1 peptide binding and receptor activation. J Biol Chem 287(6): 3642-3658.
  17. Davey, A. E., Leach, K., Valant, C., Conigrave, A. D., Sexton, P. M. and Christopoulos, A. (2012). Positive and negative allosteric modulators promote biased signaling at the calcium-sensing receptor. Endocrinology 153(3): 1232-1241.
  18. Canals, M., Lane, J. R., Wen, A., Scammells, P. J., Sexton, P. M. and Christopoulos, A. (2012). A Monod-Wyman-Changeux mechanism can explain G protein-coupled receptor (GPCR) allosteric modulation. J Biol Chem 287(1): 650-659.
  19. Valant, C., Felder, C. C., Sexton, P. M. and Christopoulos, A. (2012). Probe dependence in the allosteric modulation of a G protein-coupled receptor: implications for detection and validation of allosteric ligand effects. Mol Pharmacol 81(1): 41-52.
  20. Koole, C., Wootten, D., Simms, J., Valant, C., Miller, L. J., Christopoulos, A. and Sexton, P. M. (2011). Polymorphism and ligand dependent changes in human glucagon-like peptide-1 receptor (GLP-1R) function: allosteric rescue of loss of function mutation. Mol Pharmacol 80(3): 486-497.
  21. Dong, M., Lam, P. C., Pinon, D. I., Hosohata, K., Orry, A., Sexton, P. M., Abagyan, R. and Miller, L. J. (2011). Molecular basis of secretin docking to its intact receptor using multiple photolabile probes distributed throughout the pharmacophore. J Biol Chem 286(27): 23888-23899.
  22. Leach, K., Davey, A. E., Felder, C. C., Sexton, P. M. and Christopoulos, A. (2011). The role of transmembrane domain 3 in the actions of orthosteric, allosteric, and atypical agonists of the M4 muscarinic acetylcholine receptor. Mol Pharmacol 79(5): 855-865.
  23. Aurelio, L., Christopoulos, A., Flynn, B. L., Scammells, P. J., Sexton, P. M. and Valant, C. (2011). The synthesis and biological evaluation of 2-amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophenes as allosteric modulators of the A1 adenosine receptor. Bioorg Med Chem Lett 21(12): 3704-3707.
  24. Miller, L. J., Chen, Q., Lam, P. C., Pinon, D. I., Sexton, P. M., Abagyan, R. and Dong, M. (2011). Refinement of glucagon-like peptide 1 docking to its intact receptor using mid-region photolabile probes and molecular modeling. J Biol Chem 286(18): 15895-15907.
  25. Qi, T., Ly, K., Poyner, D. R., Christopoulos, G., Sexton, P. M. and Hay, D. L. (2011). Structure-function analysis of amino acid 74 of human RAMP1 and RAMP3 and its role in peptide interactions with adrenomedullin and calcitonin gene-related peptide receptors. Peptides 32(5): 1060-1067.
  26. Suratman, S., Leach, K., Sexton, P., Felder, C., Loiacono, R. and Christopoulos, A. (2011). Impact of species variability and ‘probe‐dependence’on the detection and in vivo validation of allosteric modulation at the M4 muscarinic acetylcholine receptor. Br J Pharmacol 162(7): 1659-1670.
  27. Wootten, D., Simms, J., Koole, C., Woodman, O. L., Summers, R. J., Christopoulos, A. and Sexton, P. M. (2011). Modulation of the glucagon-like peptide-1 receptor signaling by naturally occurring and synthetic flavonoids. J Pharmacol Exp Ther 336(2): 540-550.
  28. Aurelio, L., Valant, C., Flynn, B. L., Sexton, P. M., White, J. M., Christopoulos, A. and Scammells, P. J. (2010). Effects of conformational restriction of 2-amino-3-benzoylthiophenes on A(1) adenosine receptor modulation. J Med Chem 53(18): 6550-6559.
  29. Valant, C., Aurelio, L., Urmaliya, V. B., White, P., Scammells, P. J., Sexton, P. M. and Christopoulos, A. (2010). Delineating the mode of action of adenosine A1 receptor allosteric modulators. Mol Pharmacol 78(3): 444-455.
  30. Koole, C., Wootten, D., Simms, J., Valant, C., Sridhar, R., Woodman, O. L., Miller, L. J., Summers, R. J., Christopoulos, A. and Sexton, P. M. (2010). Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pathway-selective manner: implications for drug screening. Mol Pharmacol 78(3): 456-465.
  31. Harikumar, K. G., Ball, A. M., Sexton, P. M. and Miller, L. J. (2010). Importance of lipid-exposed residues in transmembrane segment four for family B calcitonin receptor homo-dimerization. Regul Pept 164(2-3): 113-119.
  32. Stewart, G. D., Sexton, P. M. and Christopoulos, A. (2010). Prediction of functionally selective allosteric interactions at an M3 muscarinic acetylcholine receptor mutant using Saccharomyces cerevisiae. Mol Pharmacol 78(2): 205-214.
  33. Avlani, V. A., Langmead, C. J., Guida, E., Wood, M. D., Tehan, B. G., Herdon, H. J., Watson, J. M., Sexton, P. M. and Christopoulos, A. (2010). Orthosteric and allosteric modes of interaction of novel selective agonists of the M1 muscarinic acetylcholine receptor. Mol Pharmacol 78(1): 94-104.
  34. Nawaratne, V., Leach, K., Felder, C. C., Sexton, P. M. and Christopoulos, A. (2010). Structural determinants of allosteric agonism and modulation at the M4 muscarinic acetylcholine receptor: identification of ligand-specific and global activation mechanisms. J Biol Chem 285(25): 19012-19021.
  35. Robinson, S. A., Loiacono, R. E., Christopoulos, A., Sexton, P. M. and Malone, D. T. (2010). The effect of social isolation on rat brain expression of genes associated with endocannabinoid signaling. Brain Res 1343: 153-167.
  36. Stewart, G. D., Sexton, P. M. and Christopoulos, A. (2010). Detection of novel functional selectivity at M3 muscarinic acetylcholine receptors using a Saccharomyces cerevisiae platform. ACS Chem Biol 5(4): 365-375.
  37. Gregory, K. J., Hall, N. E., Tobin, A. B., Sexton, P. M. and Christopoulos, A. (2010). Identification of orthosteric and allosteric site mutations in M2 muscarinic acetylcholine receptors that contribute to ligand-selective signaling bias. J Biol Chem 285(10): 7459-7474.
  38. Dong, M., Lam, P. C., Pinon, D. I., Orry, A., Sexton, P. M., Abagyan, R. and Miller, L. J. (2010). Secretin occupies a single protomer of the homodimeric secretin receptor complex: insights from photoaffinity labeling studies using dual sites of covalent attachment. J Biol Chem 285(13): 9919-9931.
  39. van der Westhuizen, E. T., Christopoulos, A., Sexton, P. M., Wade, J. D. and Summers, R. J. (2010). H2 relaxin is a biased ligand relative to H3 relaxin at the relaxin family peptide receptor 3 (RXFP3). Mol Pharmacol 77(5): 759-772.

  40. Refereed Reviews

  41. Wootten D, Christopoulos A, Sexton PM. Emerging paradigms in GPCR allostery: Implications for drug discovery. Nature Rev Drug Discovery (in press).
  42. Lane, J. R., Sexton, P. M. and Christopoulos, A. (2013). Bridging the gap: bitopic ligands of G-protein-coupled receptors. Trends Pharmacol Sci 34(1): 59-66.
  43. Miller LJ, Sexton PM, Dong M, Harikumar KG. The class B G protein-coupled GLP-1 receptor: an important target for the treatment of type 2 diabetes mellitus. Int J Obesity (in press, October 2012).
  44. Koole, C., Pabreja, K., Savage, E. E., Wootten, D., Furness, S. G., Miller, L. J., Christopoulos, A. and Sexton, P. M. (2013). Recent advances in understanding GLP-1R (glucagon-like peptide-1 receptor) function. Biochem Soc Trans 41(1): 172-179.
  45. Sexton, P. M., Poyner, D. R., Simms, J., Christopoulos, A. and Hay, D. L. (2012). RAMPs as drug targets. Adv Exp Med Biol 744: 61-74.
  46. Leach, K., Simms, J., Sexton, P. M. and Christopoulos, A. (2012). Structure-function studies of muscarinic acetylcholine receptors. Handb Exp Pharmacol(208): 29-48.
  47. Canals, M., Sexton, P. M. and Christopoulos, A. (2011). Allostery in GPCRs: 'MWC' revisited. Trends Biochem Sci 36(12): 663-672.
  48. Valant, C., Robert Lane, J., Sexton, P. M. and Christopoulos, A. (2012). The best of both worlds? Bitopic orthosteric/allosteric ligands of g protein-coupled receptors. Annu Rev Pharmacol Toxicol 52: 153-178.
  49. Furness, S. G., Wootten, D., Christopoulos, A. and Sexton, P. M. (2012). Consequences of splice variation on Secretin family G protein-coupled receptor function. Br J Pharmacol 166(1): 98-109.
  50. Keov, P., Sexton, P. M. and Christopoulos, A. (2011). Allosteric modulation of G protein-coupled receptors: a pharmacological perspective. Neuropharmacology 60(1): 24-35.

  51. Book Chapters

  52. D Wootten, N Tilakaratne, A Christopoulos and PM Sexton. CGRP and adrenomedullin in the brain. Handbook of Biologically Active Peptides, Ed. I.P AJ Kastin. Elsevier, San Diego, Chapter 100,  744-751.
  53. Stewart, G., Sexton, P.M. and Christopoulos, A. (2010). Inverse agonists.  Encyclopedia of Psychopharmacology, Ed. I.P. Stolerman. Springer Link Press, Germany, pp. 661-667.
  54. Gregory, K. J., Sexton, P. M. and Christopoulos, A. (2010). Overview of receptor allosterism. Current Protocols in Pharmacology, vol Chapter 1, issue Supp 51, John Wiley & Sons, Inc., USA, pp. 1.21-1-1.21-34.
  55. Leach, K., Sexton, P.M. and Christopoulos, A. (2011). Quantification of allosteric interactions at G protein-coupled receptors using radioligand binding assays. Current Protocols in Pharmacology, vol 1, issue Supp 52, John Wiley & Sons, Inc., USA, pp. 1-41.
  56. Gregory, K. J., Valant, C., Simms, J., Sexton, P. M. and Christopoulos, A. (2010). The Emergence of Allosteric Modulators for G Protein-Coupled Receptors. GPCR Molecular Pharmacology and Drug Targeting: Shifting Paradigms and New Directions: 61-87.
  57. Wootten, D. L., Simms, J., Hay, D. L., Christopoulos, A. and Sexton, P. M. (2010). Receptor activity modifying proteins and their potential as drug targets. Prog Mol Biol Transl Sci 91: 53-79.
  58. Other Publications

  59. Koole, C., Wootten, D., Sexton, P.M. cAMP accumulation assays using the ALPHAscreen? kit (PerkinElmer). Bio-protocol.org, 3(13):http://www.bio-protocol.org/wenzhang.aspx?id=805.
  60. Koole, C., Wootten, D., Sexton, P.M. pERK detection assays using the Surefire ALPHAscreen? kit (TGR Biosciences and PerkinElmer). Bio-protocol.org, 3(13):http://www.bio-protocol.org/wenzhang.aspx?id=806.
Protocols by Patrick Michael Sexton
  1. cAMP Accumulation Assays Using the AlphaScreen® Kit (PerkinElmer)
  2. pERK Detection Assays Using the Surefire AlphaScreen® Kit (TGR Biosciences and PerkinElmer)