Projects per year
Abstract
The class B secretin GPCR (SecR) has broad physiological effects, with target potential for treatment of metabolic and cardiovascular disease. Molecular understanding of SecR binding and activation is important for its therapeutic exploitation. We combined cryo-electron microscopy, molecular dynamics, and biochemical cross-linking to determine a 2.3 Å structure, and interrogate dynamics, of secretin bound to the SecR:Gs complex. SecR exhibited a unique organization of its extracellular domain (ECD) relative to its 7-transmembrane (TM) core, forming more extended interactions than other family members. Numerous polar interactions formed between secretin and the receptor extracellular loops (ECLs) and TM helices. Cysteine-cross-linking, cryo-electron microscopy multivariate analysis and molecular dynamics simulations revealed that interactions between peptide and receptor were dynamic, and suggested a model for initial peptide engagement where early interactions between the far N-terminus of the peptide and SecR ECL2 likely occur following initial binding of the peptide C-terminus to the ECD.
Original language | English |
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Article number | 4137 |
Number of pages | 17 |
Journal | Nature Communications |
Volume | 11 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Dec 2020 |
Projects
- 2 Finished
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Translating membrane proteins into therapeutics; from bedside to bench
Sexton, P., Christopoulos, A., Pantelis, C. & Parton, R. G.
1/01/19 → 31/12/23
Project: Research
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A structural understanding of class B G protein-coupled receptor function
Sexton, P., Kobilka, B., Skiniotis, G. & Furness, S.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/17 → 31/12/21
Project: Research
Equipment
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MASSIVE
Slava Kitaeff (Manager) & David Powell (Manager)
Office of the Vice-Provost (Research and Research Infrastructure)Facility/equipment: Facility
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Ramaciotti Centre for Cryo-Electron Microscopy
Georg Ramm (Manager), Simon Andrew Crawford (Operator), Hariprasad Venugopal (Operator), Joan Marea Clark (Operator) & Gediminas Gervinskas (Operator)
Faculty of Medicine Nursing and Health Sciences Research PlatformsFacility/equipment: Facility