Metabolic G Protein-Coupled Receptor Biology

Understanding GPCR structure and function

Professor Patrick M Sexton
NHMRC Senior Principal Research Fellow 
Co-Lab Head

Project areas

Laboratory overview
Laboratory overview: From a molecular understanding of receptor structure and ligand interaction to fine control of physiological response and disease treatment.

Research focus

Understanding the behaviour and quantification of allosteric drug action, and ligand-directed stimulus bias, are key areas at the forefront of GPCR research as these are considered critical to future successful drug discovery and development. Our laboratory studies these novel paradigms of GPCR function across all levels of investigation; from elucidating receptor structure, by combination of x-ray crystallography, biophysical characterisation and 3D molecular modelling, through to examination of drug behaviour in whole animal models of physiology and disease.

Our laboratory has a particular focus on Family B GPCRs that regulate the function of key peptide hormones involved in major diseases including metabolic disease (diabetes, obesity, osteoporosis), cardiovascular disease and diseases of the central nervous system.

The structural basis of receptor function

molecular model of GLP1molecular model of GLP1
Left: molecular model of the transmembrane domain of the GLP1 receptor illustrating key amino acids involved in pathway bias (green), packing and global activation (blue), ligand-induced conformational bias (red) or orthosteric versus allosteric effects. Right: molecular dynamics simulation of allosteric drug docking to the M2 muscarinic ACh receptor, video available through Nature website.

Understanding receptor structure, how ligands bind, and the dynamic changes that lead to selective engagement of signaling and regulatory partners is critical to drug design and effective control of disease.

We use a range of approaches to understand receptor function that include protein mutagenesis, use of biophysical techniques to examine receptor dynamics and x-ray crystallography to generate high resolution structural data of stable conformations.

This work is combined with 3D protein modelling to understand drug and natural ligand docking and how specific receptor residues contribute to signalling or regulatory bias.

Chemical biology and drug design

Ligands of GLP1
Distinct ligands of the GLP1 receptor cause differential activation of signaling pathways (signaling bias). The WEB of bias plot illustrates the efficacy of each of the ligands relative to GLP1 (set at 1); note the logarithmic scale.

We are currently seeking to understand the link between chemistry and the selective control of receptor function.

There are two main areas of focus; ligand-directed signal bias and allosteric regulation of receptor function.

We aim to develop SAR for ligands around parameters that describe selective signaling and allosteric co-operativity.

Cellular signalling and regulation

Both endogenous (and exogenous) peptide ligands and small molecule allosteric compounds can differentially modulate cellular function both in signal generation and signal termination (biased signaling). We are characterising ligands across a wide range of cellular endpoints (second messenger assay, receptor trafficking and regulation, cell proliferation and apoptosis, gene regulation, etc) in both recombinant and native cellular expression systems. These insights on how biased ligands control cellular function can then be used to link to understanding of systems physiology and targeted drug discovery and development.

Animal models of physiology and disease

molecular model of GLP1
Allosteric potentiation of oxyntomodulin-mediated insulin secretion by the allosteric GLP1 receptor modulator BETP in Sprague-Dawley rats.

Translation of key mechanistic findings on ligand-mediated signal bias and allosteric regulation of receptor function requires understanding of these paradigms in model systems of physiology and disease.

For the GLP1 receptor we are examining wild-type and transgenic mice to understand the impact on insulin secretion, glucose homeostasis, islet integrity, gastric emptying and neuronal activation.

Model mouse systems include GLP1R knockouts, tagged human receptor knock-ins, modified GLP1Rs that are biased for either G protein signaling or arrestin signaling, and mice with receptors with impaired dimerisation.

In work with other receptors we are looking at the effects of allosteric and biased ligands on CNS function including models of locomotion, anxiety, learning and memory and sensory gating.

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Key publications

Research papers

Liang YL, Khoshouei M, Deganutti G, Glukhova A, Koole C, Peat TS, Radjainia M, Plitzko JM, Baumeister W, Miller LJ, Hay DL, Christopoulos A, Reynolds CA, Wootten D, Sexton PM. Cryo-EM structure of the active, G(s)-protein complexed, human CGRP receptor. Nature 561:492-497, 2018.

Lei S, Clydesdale L, Dai A, Cai X, Feng Y, Yang D, Liang YL, Koole C, Zhao P, Coudrat T, Christopoulos A, Wang MW, Wootten D, Sexton PM. Two distinct domains of the glucagon-like peptide-1 receptor control peptide-mediated biased agonism. J Biol Chem 293:9370-9387, 2018.

Draper-Joyce CJ, Khoshouei M, Thal DM, Liang YL, Nguyen ATN, Furness SGB, Venugopal H, Baltos JA, Plitzko JM, Danev R, Baumeister W, May LT, Wootten D, Sexton PM, Glukhova A, Christopoulos A. Structure of the adenosine-bound human adenosine A(1) receptor-G(i) complex. Nature 558:559-563, 2018.

Liang YL, Khoshouei M, Glukhova A, Furness SGB, Zhao P, Clydesdale L, Koole C, Truong TT, Thal DM, Lei S, Radjainia M, Danev R, Baumeister W, Wang MW, Miller LJ, Christopoulos A, Sexton PM, Wootten D. Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex. Nature 555:121-125, 2018.

Liang YL, Khoshouei M, Radjainia M, Zhang Y, Glukhova A, Tarrasch J, Thal DM, Furness SGB, Christopoulos G, Coudrat T, Danev R, Baumeister W, Miller LJ, Christopoulos A, Kobilka BK, Wootten D, Skiniotis G, Sexton PM. Phase-plate cryo-EM structure of a class B GPCR-G-protein complex. Nature 546:118-123, 2017.

Glukhova A, Thal DM, Nguyen AT, Vecchio EA, Jörg M, Scammells PJ, May LT, Sexton PM, Christopoulos A. Structure of the adenosine A(1) receptor reveals the  basis for subtype selectivity. Cell 168:867-877, 2017.

Furness SGB, Liang YL, Nowell CJ, Halls ML, Wookey PJ, Dal Maso E, Inoue A, Christopoulos A, Wootten D, Sexton PM. Ligand-dependent modulation of G protein conformation alters drug efficacy. Cell 167(3):739-749, 2016.

Wootten D, Reynolds CA, Smith KJ, Mobarec JC, Koole C, Savage EE, Pabreja K,  Simms J, Sridhar R, Furness SGB, Liu M, Thompson PE, Miller LJ, Christopoulos A, Sexton PM. The extracellular surface of the GLP-1 receptor is a molecular trigger
for biased agonism. Cell 165:1632-1643, 2016.

Thal DM, Sun B, Feng D, Nawaratne V, Leach K, Felder CC, Bures MG, Evans DA, Weis WI, Bachhawat P, Kobilka TS, Sexton PM, Kobilka BK, Christopoulos A. Crystal structures of the M1 and M4 muscarinic acetylcholine receptors. Nature 531:335-40, 2016.

Wootten D, Reynolds CA, Koole C, Smith KJ, Mobarec JC, Simms J, Quon T, Coudrat T, Furness SG, Miller LJ, Christopoulos A, Sexton PM. A hydrogen-bonded polar network in the core of the glucagon-like peptide-1 receptor is a fulcrum for biased agonism: lessons from class B crystal structures. Mol Pharmacol 89:335-47, 2016.

Dror RO, Green HF, Valant C, Borhani DW, Pan AC, Arlow DH, Valcourt JR, Canals M, Lane JR, Rahmani R, Baell JB, Sexton PM, Christopoulos A, Shaw DE. Structural basis for modulation of a GPCR by allosteric drugs. Nature 503:295-299, 2013.

Kruse AC, Ring AM, Manglik A, Hu J, Hu K, Eitel K, Hübner H, Pardon E, Valant C, Sexton PM, Christopoulos A, Felder CC, Gmeiner P, Steyaert J, Weis WI, Garcia KC, Wess J, Kobilka BK. Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature 504:101-106, 2013.

Wootten D, Simms J, Miller LJ, Christopoulos, A and Sexton PM. Polar transmembrane interactions drive formation of ligand-specific and signal pathway-biased Family B GPCR conformations. Proc Natl Acad Sci USA 110: 5211-5216, 2013.

Harikumar KG, Wootten D, Pinon DI, Koole C, Ball AM, Furness SGB, Graham B, Dong M, Christopoulos A, Miller LJ, Sexton PM. Glucagon-like peptide-1 receptor dimerisation differentially regulates agonist signalling but does not affect small molecule allostery. Proc Natl Acad Sci USA 109: 18607-18612, 2012.

Wootten D, Savage EE, Valant C, May LT, Sloop KW, Ficorilli J, Showalter AD, Willard FS, Christopoulos A, Sexton PM. Allosteric modulation of endogenous metabolites as an avenue for drug discovery. Mol Pharmacol 82:281-290, 2012.

Wootten D, Savage EE, Willard FS, Bueno AB, Sloop KW, Christopoulos A, Sexton PM. Differential activation and modulation of the glucagon-like peptide-1 receptor by small molecule ligands. Mol Pharmacol 83:822-834, 2013.

Wootten D, Savage EE, Valant C, May LT, Sloop KW, Ficorilli J, Showalter AD, Willard FS, Christopoulos A, Sexton PM. Allosteric modulation of endogenous metabolites as an avenue for drug discovery. Mol Pharmacol 82:281-290, 2012.

Koole C, Wootten D, Simms J, Miller LJ, Christopoulos A, Sexton PM. The second extracellular loop of the human glucagon-like peptide-1 receptor (GLP-1R) has a critical role in GLP-1 peptide binding and receptor activation. J Biol Chem 287:3642-3648, 2012.

Koole C, Wootten D, Simms J, Savage EE, Miller LJ, Christopoulos A, Sexton PM. The second extracellular loop of the human glucagon-like peptide-1 receptor (GLP-1R) differentially regulates orthosteric but not allosteric agonist binding and function. J Biol Chem 287:3659-3673, 2012.

Koole C, Wootten D, Simms J, Valant C, Miller LJ, Christopoulos A, Sexton PM. 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: 486-497, 2011.


Wootten D, Christopoulos A, Marti-Solano M, Babu MM, Sexton PM. Mechanisms of signalling and biased agonism in G protein-coupled receptors. Nat Rev Mol Cell Biol 19:638-653, 2018.

Thal DM, Glukhova A, Sexton PM, Christopoulos A. Structural insights into G-protein-coupled receptor allostery. Nature 559:45-53, 2018.

Riddy DM, Delerive P, Summers RJ, Sexton PM, Langmead CJ. G protein-coupled receptors targeting insulin resistance, obesity, and Type 2 diabetes mellitus. Pharmacol Rev 70:39-67, 2018.

Wootten D, Miller LJ, Koole C, Christopoulos A, Sexton PM. Allostery and biased agonism at class B G protein-coupled receptors. Chem Rev 117:111-138, 2017.

Kruse AC, Kobilka BK, Gautam D, Sexton PM, Christopoulos A, Wess J. Muscarinic acetylcholine receptors: novel opportunities for drug development. Nat Rev Drug Discov 13:549-60, 2014.

Wootten D, Christopoulos A, Sexton PM. Emerging paradigms in GPCR allostery: implications for drug discovery. Nature Rev Drug Discov 12:630-644, 2013.

Sexton PM, Wootten D. Structural biology: meet the B family. Nature 499:417-418, 2013.

Koole C, Savage EE, Christopoulos A, Miller LJ, Sexton PM, Wootten D. Signal bias, allosterism and polymorphic variation at the GLP-1R: Implications for drug discovery. Mol Endocrinol 27:1234-1244, 2013.

Lane JR, Sexton PM, Christopoulos A. Bridging the gap: Bitopic ligands of G protein-coupled receptors. Trends Pharmacol Sci 34:59-66, 2013.

Valant C, Lane JR, Sexton PM, Christopoulos A. The best of both worlds? Biotopic orthosteric/allosteric ligands of G protein-coupled receptors. Ann Rev Pharmacol Toxicol 52:153-78, 2012.

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Understanding GPCR allostery and signal bias

GPCR drug discovery

Structural basis of GPCR function

  • Professor Arthur Christopoulos, Drug Discovery Biology, MIPS
  • Professor Larry Miller, Mayo Clinic, USA
  • Professor Brian Kobilka, Stanford University, USA
  • Professor Ruben Abagyan, Univ. California, San Diego, USA
  • Dr Ron Dror, DE Shaw Research, USA
  • Dr Celine Valant, Drug Discovery Biology, MIPS

Modulation of glucagon-like peptide 1 receptor signaling, regulation and physiology to treat metabolic disease

Targeting adenosine receptors to treat ischemia/reperfusion

Modulation of muscarnic acetylcholine receptor signaling, regulation and physiology to treat neuropsychitric disease

Allosteric control of calcium receptor function

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Lab members

Dr Dana Hutchinson
Research Fellow

Dr Lynda Whiting
Research Fellow

Dr Lynn Liang
Research Fellow

Dr Elva Zhao
Research Fellow

Dr Caroline Hick
Research Fellow

Dr Madeleine Fletcher
Research Fellow

Dr Masa Sato
Research Fellow

Dr Seungmin Ham
Research Fellow

George Christopoulos
Lab manager

Tin Truong
Research assistant

Villy Julita
Research assistant

Jie Gao
HDR student

Lachlan Clydesdale
HDR student

Xin Zhang
HDR student

  • Belinda Dennis - Honours student
  • Diana Ngoc Thu Tran - Honours student
  • Felix Bennetts - Honours student
  • Grace Mennen - Honours student
  • Qikui Xu - Honours student

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  • NHMRC Senior Principal Research Fellowship (Patrick Sexton) (2019 – 2023)
  • NHMRC Senior Research Fellowship (Denise Wootten) (2019 – 2023)
  • NHMRC Principal Research Fellowship (Patrick Sexton) (2009 – 2013; 2014 – 2018)
  • NHMRC Program Grant (2019 – 2023): Translating membrane proteins into therapeutics: from bedside to bench
  • NHMRC Program Grant (2014 – 2018): The Janus Faces of G Protein-Coupled Receptors: Implications for Disease Mechanisms and Opportunities.
  • NHMRC Program Grant (2009 – 2013): Understanding G protein-coupled receptors (GPCRs): accelerating discovery from concept to clinic.
  • NHMRC Project Grant (2011 – 2013): Molecular characterisation of the glucagon-like peptide 1 receptor.
  • NHMRC Project Grant (2014 – 2016): Understanding the structural basis for Family B G protein-coupled receptor function.
  • ARC Linkage Grant (2012 – 2015): Subtypes selectivity and functional bias of receptor positive allosteric modulators for understanding models of pulmonary disease.
  • Alchemia/Audeo Discovery (2010-2015): GPCR drug discovery.
  • Servier (2012-2016): GPCR drug discovery.
  • Eli Lilly (2013-2014): Development of transgenic mice expressing biased GLP1 receptors.

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