Publications

Monash Node

Original research papers on cryo-EM of membrane proteins

 

  • Zhang X, Belousoff MJ, Liang Y-L, Danev R*, Sexton PM*, Wootten D*. Structure and dynamics of semaglutide and taspoglutide bound GLP-1R-Gs complexes. BioRxiv01.12.426449; doi: https://doi.org/10.1101/2021.01.12.426449.
  • Zhang X, Johnson RM, Drulyte I, Yu L, Kotecha A, Danev R, Wootten D*, Sexton PM*, Belousoff MJ*. Evolving cryo-EM structural approaches for GPCR drug discovery. BioRxiv01.11.426276; doi: https://doi.org/10.1101/2021.01.11.426276.
  • Danev R, Belousoff MJ, Liang Y-L, Zhang X, Wootten D, Sexton PM. Routine sub-2.5 Å cryo-EM structure determination of B-family G protein-coupled receptors. BioRxivorg/10.1101/2020.08.21.260851
  • Zhang X, Belousoff MJ, Zhao P, Kooistra AJ, Truong TT, Ang SY, Underwood CR, Egebjerg T, Senel P, Stewart GD, Liang Y-L, Glukhova A, Venugopal H, Christopoulos A, Furness SGB, Miller LJ, Reedtz-Runge S, Langmead CJ, Gloriam DE, Danev R*, Sexton PM*, Wootten D*. Differential GLP-1R binding and activation by peptide and non-peptide agonists. Mol Cell 80: 485-500.e7. (doi: 10.1016/j.molcel.2020.09.020).
  • Dong M, Deganutti G, Piper SJ, Liang Y-L, Khoshouei M, Belousoff MJ, Harikumar KG, Reynolds CA, Glukhova A, Furness SGB, Christopoulos A, Danev R, Wootten D*, Sexton PM*, Miller LJ*. Structure and dynamics of the active, Gs-coupled, human secretin receptor. Nat Commun 11: 4137, 2020 (doi:10.1038/s41467-202-17791-4).
  • Chang R, Zhang X, Qiao A, Dai A, Belousoff MJ, Tan Q, Shao L, Zhong L, Lin G, Liang Y-L, Ma L, Han S, Yang D, Danev R, Wang M-W*, Wootten D*, Wu B*, Sexton PM*. Cryo-electron microscopy structure of the glucagon receptor with a dual-agonist peptide. J Biol Chem 295: 9313-9325, 2020.
  • Liang Y-L, Belousoff MJ, Fletcher MM, Zhang X, Khoshouei M, Deganutti G, Koole C, Furness SGB, Miller LJ, Hay DL, Christopoulos A, Reynolds CA, Danev R, Wootten D*, Sexton PM*. Structure and dynamics of adrenomedullin receptors AM1 and AM2 reveal key mechanisms in the control of receptor phenotype by receptor activity-modifying proteins. ACS Pharmacol Transl Sci 3: 263-284, 2020.
  • Qiao A, Han S, Li X, Li Z, Zhao P, Dai A, Chang R, Tai L, Tan Q, Chu X, Ma L, Thorsen TS, Reedtz-Runge S, Yang D, Wang M-W, Sexton PM, Wootten D*, Sun F*, Zhai Q*, Wu B*. Structural basis of Gs and Gi recognition by the human glucagon receptor. Science 367: 1346-1352, 2020.
  • Liang Y-L, Belousoff MJ, Zhao P, Koole C, Fletcher MM, Truong TT, Julita V, Christopoulos G, Xu HE, Zhang Y, Khoshouei M, Christopoulos A, Danev R*, Sexton PM*, Wootten D*. Towards a structural understanding of class B GPCR peptide binding and activation. Mol Cell 77: 656-668, 2020.
  • Ma S, Shen Q, Zhao L-H, Mao C, Zhou XE, Shen D-D, de Waal PW, Bi P, Li C, Jiang Y, Wang M-W, Sexton PM, Wootten D, Melcher K, Zhang Y, Xu HE. Molecular basis for hormone recognition and activation of corticotropin-releasing factor receptors. Mol Cell 77: 669-680, 2020.
  • Zhao P, Liang Y-L, Belousoff MJ, Deganutti G, Fletcher MM, Willard FS, Bell MG, Christe ME, Sloop KW, Inoue A, Truong TT, Clydesdale L, Furness SGB, Christopoulos A, Wang M-W, Miller LJ, Reynolds CA, Danev R*, Sexton PM*, Wootten D*. Activation of GLP-1 receptor by a non-peptide agonist. Nature 577: 432-436, 2020.
  • Ramirez-Aportela E Vilas JL, Glukhova A, Melero R, Conesa P, Martinez M, Maluenda D, Mota J, Jimenez A, Vargas J, Marabini R, Sexton PM, Carazo JM, Sorzano COS. Automatic local resolution-based sharpening of cryo-EM maps. Bioinformatics 36: 765-772, 2020.
  • Dal Maso E, Glukhova A, Zhu Y, Garcia-Nafria J, Tate CG, Atanasio S, Reynolds CA, Ramirez-Aportela E, Carazo J-M, Hick CA, Furness SGB, Hay DL, Liang Y-L, Miller LJ, Christopoulos A, Wang M-W, Wootten D*, Sexton PM*. The molecular control of calcitonin receptor (CTR) signaling. ACS Pharmacol Transl Sci 2: 31-51, 2019.
  • Liang Y-L, Zhao P, Draper-Joyce CJ, Baltos J, Glukhova A, Troung TT, May LT, Christopoulos A, Wootten D*, Sexton PM*, Furness SGB*. Dominant negative G proteins enhance formation and purification of agonist-GPCR-G protein complexes for structure determination. ACS Pharmacol Transl Sci 1: 12-20, 2018.
  • Liang Y-L, 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, Gs-protein complexed, human CGRP receptor. Nature 561: 492-497, 2018.
  • Draper-Joyce CJ, Khoshouei M, Thal D, Liang Y-L, Nguyen ATN, Furness SGB, Venugopal H, Baltos J, Plitzko JM, Danev R, Baumeister W, May LT, Wootten D, Sexton PM*, Glukhova A*, Christopoulos A*. Structure of the adenosine-bound human adenosine A1 receptor-Gi complex. Nature 558: 559-563, 2018.
  • Liang Y-L, Khoshouei M, Glukhova A, Furness SGB, Zhao P, Clydesdale L, Koole C, Troung TT, Thal DM, Lei S, Radjainia M, Danev R, Baumeister W, Wang M-W, 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 Y-L, 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. Nature546: 118-123, 2017.

 

Selected additional research publications

 

  • Bradley SJ, Molloy C, Valuskova P, Dwomoh L, Scarpa M, Rossi M, Finlayson L, Svensson KA, Chernet E, Barth VN, Gherbi K, Sykes DA, Wilson CA, Mistry R, Sexton PM, Christopoulos A, Mogg AJ, Rosethorne EM, Sakata S, Challiss RAJ, Broad LM, Tobin AB. Employing chemogenetic and G protein-biased mice in the design of next generation M1-muscaranic acetylcholine receptor drugs. Nat Chem Biol 16: 240-249, 2020.
  • Vukovic Z, Gentry PR, Berizzi AE, Hirat K, Varghese S, Thompson G, van der Westhuizen ET, Burger WAC, Rahmani R, Valant C, Langmead C, Lindsley C, Baell J, Tobin AB, Sexton PM, Christopoulos A, Thal DT. Crystal structure of the M5 muscarinic acetylcholine receptor. Proc Natl Acad Sci USA 116: 26001-26007, 2019.
  • Hollingsworth SA, Kelly B, Valant C, Michaelis JA, Mastromihalis O, Thompson G, Venkatakrishnan AJ, Hertig S, Scammells PJ, Sexton PM, Felder CC, Christopoulos A, Dror RO. Cryptic pocket formation underlies allosteric modulatory selectivity at muscarinic GPCRs. Nat Commun 10: 3289, 2019 (doi: 10.1038/s41467-019-11062-7).
  • Liu S, Jean-Alphonse FG, White AD, Wootten D, Sexton PM, Gardella TJ, Vilardaga JP, Gellman SH. Use of backbone modification to enlarge the spatiotemporal diversity of parathyroid hormone receptor-1 signaling via biased agonism. J Am Chem Soc 141: 14486-14490, 2019.
  • Levine PM, Balana AT, Sturchler E, Koole C, Noda H, Zarzycka B, Daley EJ, Truong TT, Katritch V, Gardella TJ, Wootten D, Sexton PM, McDonald P, Pratt MR. O-GlcNAc engineering of GPCR peptide-agonists improves their stability and in vivo J Am Chem Soc 141: 14210-14291, 2019.
  • Korczynska M, Clark MJ, Valant C, Xu J, Moo EV, Abold S, Weiss DR, Torosyan H, Huang W, Kruse AC, Lyda BR, May LT, Baltos J, Sexton PM, Kobilka BK, Christopoulos A, Shoichet BK, Sunahara RK. Structure-based discovery of selective positive allosteric modulators of antagonists for the M2 muscarinic acetylcholine receptor. Proc Natl Acad Sci USA 115: E2419-E2428, 2018.
  • Glukhova A, Thal DM, Nguyen AT, Vecchio EA, Jörg M, Scammells PJ, May LT, Sexton PM*, Christopoulos A*. Structure of the adenosine A1 receptor reveals the basis for subtype selectivity. Cell 168: 867-877, 2017.
  • Bradley SJ, Bourgognon J-M, Sanger HE, Verity N, Mogg AJ, White DJ, Butcher AJ, Moreno JA, Molloy C, Macedo-Hatch T, Edwards JM, Wess J, Pawlak R, Read DJ, Sexton PM, Broad LM, Steinert JR, Mallucci GR, Christopoulos A, Felder CC, and Tobin AB. M1-muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss. J Clin Invest 127: 487-499, 2017.
  • Qin CX, May LT, Li R, Cao N, Rosli S, Deo M, Alexander AE, Horlock D, Bourke JE, Yang YH, Stewart AG, Kaye DM, Du Z-J, Sexton PM, Christopoulos A, Gao Z-M, Ritchie RH. Small-molecule biased formyl peptide receptor agonist compound 17b protects against myocardial ischemia-reperfusion injury in mice. Nature Commun 8: 14232. doi: 10.1038/ncomms14232, 2017.
  • Hager MV, Johnson LM, Wootten D*, Sexton PM*, Gellman SH*. β-Arrestin-biased agonists of the GLP-1 receptor from β-amino acid residue incorporation into GLP-1 analogues. J Am Chem Soc 138: 14970-14979, 2016.
  • 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 167: 739-749, 2016.
  • Miao Y, Goldfeld D, Moo EV, Sexton PM, Christopoulos A, McCammon JA, and Valant Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor. Proc Natl Acad Sci USA 113: E5675-684, 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 GLP-1 receptor extracellular surface is a molecular trigger for biased agonism. Cell 165: 1632-1643, 2016.
  • Leach K, Gregory KJ, Kufareva I, Khajehali E, Cook AE, Abagyan R, Conigrave AD, Sexton PM, Christopoulos A. Towards a structural understanding of allosteric drugs at the human calcium sensing receptor. Cell Res 26: 574-592, 2016.
  • Klein Herenbrink C, Sykes DA, Donthamsetti P, Canals M, Coudrat T, Shonberg J, Scammells PJ, Capuano B, Sexton PM, Charlton SJ, Javitch JA, Christopoulos A, Lane The vital role of kinetic context in biased agonism at GPCRs. Nature Commun 7: 10842, 2016. doi: 10.1038/ncomms10842.
  • 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 and insights into their allosteric modulation. Nature 531: 335-340, 2016.
  • Lane JR, Donthamsetti P, Shonberg J, Draper-Joyce CJ, Dentry S, Michino M, Shi L, López L, Scammells PJ, Capuano B, Sexton PM, Javitch JA, Christopoulos A. A new mechanism of allostery in a G protein-coupled receptor dimer. Nature Chem Biol. 10: 745-52, 2014.
  • Valant C, May LT, Aurelio L, Chuo C, White PJ, Baltos J, Sexton PM, Scammells PJ, Christopoulos A. Separation of on-target efficacy from adverse effects through rational design of a bitopic adenosine receptor agonist. Proc Natl Acad Sci USA 111: 4614-4619, 2014.
  • 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.
  • 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.
  • 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 109: 18607-18612, 2012.

 

Selected Reviews

 

  • Glukhova A*, Draper-Joyce CJ, Sunahara RK, Christopoulos A, Wootten D, Sexton PM*. Rules of engagement: GPCRs and G proteins. ACS Pharmacol Transl Sci 1: 73-83, 2018.
  • Wootten D*, Christopoulos A, Marti-Solano M, Babu MM, Sexton PM*. Mechanisms of signalling and biased agonism in G-protein-coupled receptors. Nature 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.
  • Thal DM*, Vuckovic Z, Draper-Joyce CJ, Liang Y-L, Glukhova A, Christopoulos A, Sexton PM*. Recent advances in the determination of G Protein-coupled receptor structures. Curr Opin Struct Biol 51: 28-34, 2018.
  • Sexton PM, Christopoulos A. To bind or not to bind: Unravelling GPCR polypharmacology. Cell 172: 636-638, 2018.
  • Riddy DM, Delerive P, Summers RJ, Sexton PM, Langmead CJ. G protein-coupled receptors in targeting insulin resistance, obesity and type 2 diabetes mellitus. Pharmacol Rev 70: 39-67, 2018.
  • Lane JR, May LT, Parton RG, Sexton PM, Christopoulos A. A kinetic view of GPCR allostery and biased agonism. Nature Chem Biol 13: 929-937, 2017.
  • 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.
  • De Graff C, Donnelly D, Wootten D, Lau J, Sexton PM, Miller LJ, Ahn J-M, Liao J, Fletcher MM, Yang D, Brown AJH, Zhou C, Deng J, Wang M-W. Glucagon-like peptide-1 and its class B G protein-coupled receptors: a long march to therapeutic success. Pharmacol Rev 68: 954-1013, 2016.
  • 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.
  • Christopoulos A, Changeux JP, Catterall WA, Fabbro D, Burris TP, Cidlowski JA, Olsen RW, Peters JA, Neubig RR, Pin JP, Sexton PM, Kenakin TP, Ehlert FJ, Spedding M, Langmead CJ. International Union of Basic and Clinical Pharmacology. XC. Multisite Pharmacology: Recommendations for the nomenclature of receptor allosterism and allosteric ligands. Pharmacol Rev. 66: 918-47, 2014.
  • Sexton PM, Wootten D. Structural biology: meet the B family. Nature 499:417-418, 2013.
  • Wootten D, Christopoulos A, Sexton PM. Emerging paradigms in GPCR allostery: implications for drug discovery. Nature Rev Drug Discov 12: 630-644, 2013.

University of Wollongong Node

  • Single-molecule visualization of conformational changes and substrate transport in the vitamin B12 ABC importer BtuCD-F. Goudsmits JMH, Slotboom DJ, van Oijen AM. Nat Commun. 2017 Nov 21;8(1):1652. doi: 10.1038/s41467-017-01815-7.
  • Unsynchronised subunit motion in single trimeric sodium-coupled aspartate transporters. Erkens GB, Hänelt I, Goudsmits JM, Slotboom DJ, van Oijen AM. Nature. 2013 Oct 3;502(7469):119-23. doi: 10.1038/nature12538.
  • Huynh TG, Cuny H, Slesinger PA, Adams DJ. (2015) Novel mechanism of Cav2.2 inhibition revealed through a-conotoxin Vc1.1 activation of the GABAB receptor. Molecular Pharmacology 87, 240-250. [PMID: 25425625]

  • Castro J, Harrington AM, Garcia-Caraballo S, Maddern J, Grundy L, Zhang J, Page G, Miller P, Craik DJ, Adams DJ, Brierley SM. (2017) α-Conotoxin Vc1.1 inhibits human dorsal root ganglion neuroexcitability and mouse colonic nociception via GABAB receptors. Gut 66, 1083-1094. [PMID: 26887818]

  • Sadeghi M, McArthur JR, Finol-Urdaneta RK, Adams DJ. (2017)  Analgesic conopeptides targeting G protein-coupled receptors reduce excitability of sensory neurons. Neuropharmacology 127, 116-123. [PMID: 28533165]

  • Sadeghi M, Carstens BB, Callaghan BP, Daniel JT, Tae H-S, O’Donnell T, Castro J, Brierley SM, Adams DJ, Craik DJ, Clark RJ. (2018) Structure-activity studies reveal the molecular basis for GABAB receptor-mediated inhibition of high voltage-activated calcium channels by a-conotoxin Vc1.1. ACS Chemical Biology 13(6), 1577-1587. [PMID: 29746088]

The University of Melbourne Node

  • A “Drug Sweeping” State of the TriABC Triclosan Efflux Pump from Pseudomonas aeruginosa. Structure 2020. DOI: 10.1016/j.str.2020.09.001

  • An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity. CELL HOST & MICROBE 2019. DOI: 10.1016/j.chom.2019.03.002

  • Evans, J.C., Johnstone, B.A., Lawrence, S.L., Morton, C.J., Christie, M.P., Parker, M.W.* & Tweten, R.K.* (2020) (*Joint senior authors) A key motif in cholesterol-dependent cytolysins reveals a large family of related proteins. mBio. 11, e02351-20.
  • Miles, L.A., Hermans, S., Crespi, G.A.N., Gooi, J.H., Doughty, L., Nero, T.L., Markulić, J., Ebneth, A., Wroblowski, B., Oehlrich, D., Trabanco, A.A., Rives, M-L., Royaux, I., Hancock, N.C., & Parker, M.W. (2019) Small molecule binding to Alzheimer’s risk factor CD33 promotes AbiScience 19, 110-118.
  • Metcalfe, R. D., Aizel, K., Zlatic, C. O., Nguyen, P. M., Morton, C. J., Lio, D. S., Cheng, H. C., Dobson, R., Parker, M. W., Gooley, P. R., Putoczki, T. L., & Griffin, M. D. W. (2020). The structure of the extracellular domains of human interleukin 11α receptor reveals mechanisms of cytokine engagement. The Journal of Biological Chemistry, 295(24), 8285–8301. https://doi.org/10.1074/jbc.RA119.012351

  • Metcalfe, R. D., Putoczki, T. L., & Griffin, M. D. W. (2020). Structural Understanding of Interleukin 6 Family Cytokine Signaling and Targeted Therapies: Focus on Interleukin 11. Frontiers in Immunology, 11, 1424. https://doi.org/10.3389/fimmu.2020.01424