Projects per year
Abstract
Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, such as osteoporosis, diabetes and obesity. Here we report the structure of a full-length class B receptor, the calcitonin receptor, in complex with peptide ligand and heterotrimeric Gα s βÎ 3 protein determined by Volta phase-plate single-particle cryo-electron microscopy. The peptide agonist engages the receptor by binding to an extended hydrophobic pocket facilitated by the large outward movement of the extracellular ends of transmembrane helices 6 and 7. This conformation is accompanied by a 60° kink in helix 6 and a large outward movement of the intracellular end of this helix, opening the bundle to accommodate interactions with the α5-helix of Gα s. Also observed is an extended intracellular helix 8 that contributes to both receptor stability and functional G-protein coupling via an interaction with the Gβ subunit. This structure provides a new framework for understanding G-protein-coupled receptor function.
Original language | English |
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Pages (from-to) | 118-123 |
Number of pages | 6 |
Journal | Nature |
Volume | 546 |
Issue number | 7656 |
DOIs | |
Publication status | Published - 1 Jun 2017 |
Projects
- 5 Finished
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Understanding allosteric modulation and biased signalling at Family B GPCRs
Wootten, D. (Primary Chief Investigator (PCI))
National Health and Medical Research Council (NHMRC) (Australia)
1/01/15 → 31/12/18
Project: Research
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Understanding the structural basis for Family B G protein-coupled receptor function
Sexton, P. (Primary Chief Investigator (PCI)), Furness, S. (Chief Investigator (CI)), Kobilka, B. (Chief Investigator (CI)) & Wootten, D. (Chief Investigator (CI))
National Health and Medical Research Council (NHMRC) (Australia)
1/01/14 → 31/12/16
Project: Research
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The Janus face of G Protein-Coupled Receptors: Implications for Disease Mechanisms and Opportunities for Drug Discovery
Sexton, P. (Primary Chief Investigator (PCI)), Bunnett, N. (Chief Investigator (CI)), Christopoulos, A. (Chief Investigator (CI)) & Summers, R. (Chief Investigator (CI))
National Health and Medical Research Council (NHMRC) (Australia)
1/01/14 → 31/12/18
Project: Research