6WI9

Human secretin receptor Gs complex

Summary for 6WI9

• Entry DOI: 10.2210/pdb6wi9/pdb
• EMDB information: 21683
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, gs coupled, complex, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 161076.54

Authors

Belousoff, M.J.,Khoshouei, M. (deposition date: 2020-04-09, release date: 2020-08-12, Last modification date: 2025-05-21)

Primary citation

Dong, M.,Deganutti, G.,Piper, S.J.,Liang, Y.L.,Khoshouei, M.,Belousoff, M.J.,Harikumar, K.G.,Reynolds, C.A.,Glukhova, A.,Furness, S.G.B.,Christopoulos, A.,Danev, R.,Wootten, D.,Sexton, P.M.,Miller, L.J.
Structure and dynamics of the active Gs-coupled human secretin receptor.
Nat Commun, 11:4137-4137, 2020

PubMed 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.

PubMed: 32811827
DOI: 10.1038/s41467-020-17791-4

Experimental method

ELECTRON MICROSCOPY (4.3 Å)