Projects per year
Abstract
G protein-coupled receptors (GPCRs) are critical regulators of cellular function acting via heterotrimeric G proteins as their primary transducers with individual GPCRs capable of pleiotropic coupling to multiple G proteins. Structural features governing G protein selectivity and promiscuity are currently unclear. Here, we used cryo-electron microscopy (cryo-EM) to determine structures of the cholecystokinin (CCK) type 1 receptor (CCK1R) bound to the CCK peptide agonist, CCK-8 and 2 distinct transducer proteins, its primary transducer Gq, and the more weakly coupled Gs. As seen with other Gq/11-GPCR complexes, the Gq-a5 helix (aH5) bound to a relatively narrow pocket in the CCK1R core. Surprisingly, the backbone of the CCK1R and volume of the G protein binding pocket were essentially equivalent when Gs was bound, with the Gs aH5 displaying a conformation that arises from "unwinding" of the far carboxyl-terminal residues, compared to canonically Gs coupled receptors. Thus, integrated changes in the conformations of both the receptor and G protein are likely to play critical roles in the promiscuous coupling of individual GPCRs.
Original language | English |
---|---|
Article number | e3001295 |
Number of pages | 28 |
Journal | PLoS Biology |
Volume | 19 |
Issue number | 6 |
DOIs | |
Publication status | Published - 4 Jun 2021 |
-
ARC Industrial Transformation Training Centre for Cryo-Electron Microscopy of Membrane Proteins for Drug Discovery
Sexton, P. (Primary Chief Investigator (PCI)), Rouiller, I. (Chief Investigator (CI)), Wootten, D. (Chief Investigator (CI)), van Oijen, A. (Chief Investigator (CI)), Parker, M. W. (Chief Investigator (CI)), Lucet, I. (Partner Investigator (PI)), Griffin, M. (Chief Investigator (CI)), Adams, D. J. (Chief Investigator (CI)), Czabotar, P. E. (Partner Investigator (PI)), Flocco, M. (Partner Investigator (PI)), Han, S. (Partner Investigator (PI)), Shepherd, R. (Partner Investigator (PI)), Ciferri, C. (Partner Investigator (PI)), Williams, P. A. (Partner Investigator (PI)), Brown, D. (Partner Investigator (PI)), Schreuder, H. (Partner Investigator (PI)), Reedtz-Runge, S. (Partner Investigator (PI)), Drinkwater, C. (Partner Investigator (PI)), Howard, B. L. (Partner Investigator (PI)), Betigeri, G. (Partner Investigator (PI)), Pryor, E. (Partner Investigator (PI)), How, J. (Project Manager) & Christopoulos, T. (Chief Investigator (CI))
Boehringer Ingelheim (Germany), AstraZeneca (United Kingdom)
23/03/21 → 23/03/27
Project: Research
-
Using protein structure and dynamics to facilitate drug discovery
Thal, D. (Primary Chief Investigator (PCI))
1/01/21 → 31/12/25
Project: Research
-
Novel targeting of the glucagon family of G protein coupled receptors
Wootten, D. (Primary Chief Investigator (PCI))
National Health and Medical Research Council (NHMRC) (Australia)
1/01/19 → 31/12/23
Project: Research