Denise Wootten

Position

NHMRC Senior Research Fellow

Head: Metabolic Receptor Biology Laboratory

Drug Discovery Biology

Monash Institute of Pharmaceutical Sciences

Faculty of Pharmacy and Pharmaceutical Sciences

Denise Wootten completed her PhD in 2008 at the University of Birmingham in the UK before moving to MIPS in 2009. Her expertise is in the study of G protein-coupled receptors (GPCRs). These proteins represent the largest family of receptors in the human genome and the biggest class of current drug targets.

Denise's laboratory focuses on studying the class B subfamily of receptors that regulate the function of key peptide hormones that are involved in many physiological processes. The specific receptors that the research is principally focused include the glucagon and calcitonin receptor families that are important clinical targets for metabolic diseases (diabetes, obesity, osteoporosis). The laboratory uses a multidisciplinary approach that encompasses structural and computational biology, molecular and mathematical modelling, biochemistry  and cellular signal transduction, native tissue bioassays and preclinical animal models to study and understand two key paradigms of drug action at these receptors, specifically, allosteric modulation and biased agonism. These phenomenon are key areas at the forefront of GPCR research as these are considered critical to future successful drug discovery and development.

Selected recent original research articles

1) Yi-Lynn Liang, Maryam Khoshouei, Giuseppe Deganutti, Alisa Glukhova, Cassandra Koole, Thomas S. Peat, Mazdak Radjainia, Jürgen M. Plitzko, Wolfgang Baumeister, Laurence J. Miller, Deborah l. Hay, Arthur Christopoulos, Christopher A. Reynolds, Denise Wootten* & Patrick M. Sexton*. Cryo-EM structure of the active, Gs- protein complexed, human CGRP receptor. Nature (2018) Sep;561(7724):492-497.

2) Yi-Lynn Liang, Maryam Khoshouei, Alisa Glukhova, Sebastian G. B. Furness, Peishen Zhao, Lachlan Clydesdale, Cassandra Koole, Tin T. Truong, David M Thal, Saifei Lei, Mazdak Radjainia, Radostin Danev, Wolfgang Baumeister, Ming-Wei Wang, Laurence J. Miller, Arthur Christopoulos, Patrick M. Sexton, Denise Wootten. Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex. Nature (2018) Mar 1:555(7694):121-125.

3) Dal Maso E, Zhu Y, Pham V, Reynolds CA, Deganutti  G, Hick CA, Yang D, Christopoulos A, Hay DL, Wang MW, Sexton PM, Furness SGB, Wootten D. Exracellular loops 2 and 3 of the calcitonin receptor selectively modify agonist binding and efficacy. Biochem Pharmacol. (2018) 150; 214-244.

4) Fletcher MM, Halls ML, Zhao P, Clydesdale L, Christopoulos A, Sexton PM, Wootten D. Glucagon-like peptide-1 receptor internalisation controls spatiotemporal signalling mediated by biased agonists. Biochem Pharmacol. (2018) 156:406-419.

5) 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 (2017) 546(7656):118-123.

6) Wootten D, Reynolds CA, Smith KJ, Mobarec JC, Koole C, Savage EE, Pabreja K, Simms J, Sridhar R, Furness SG, 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 (2016) 165(7):1632-43.

7) Furness SGB, Liang Y-L, 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 (2016) 167(3):739-749.

Selected recent review articles

8)  Wootten D*, Christopoulos A, Marti-Solano M, Babu MM, Sexton PM*. Mechanisms and signalling and biased agonism in G protein-coupled receptors. Nat Rev Mol Cell Biol. (2018) 19(10):638-653

9)  Wootten D*, Miller LJ, Koole C, Christopoulos A, Sexton PM*. Allostery and Biased Agonism at Class B G Protein-Coupled Receptors. Chem Rev. (2017) 117(1):111-138.

10) Graaf Cd*, Donnelly D*, Wootten D*, Lau J, Sexton PM, Miller LJ, Ahn JM, Liao J, Fletcher MM, Yang D, Brown AJ, Zhou C, Deng J, Wang MW. Glucagon-like Peptide-1 and its Class B G Protein-coupled Receptor: A Long March to Therapeutic Success. Pharmacol Rev. (2016) 68(4):954-1013.