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Structure and dynamics of the active Gs-coupled human secretin receptor

Dong, Maoqing and Deganutti, Giuseppe and Piper, Sarah J and Liang, Yi-Lynn and Khoshouei, Maryam and Belousoff, Matthew J and Harikumar, Kaleeckal G and Reynolds, Christopher A and Glukhova, Alisa and Furness, Sebastian GB and Christopoulos, Arthur and Danev, Radostin and Wootten, Denise and Sexton, Patrick M and Miller, Laurence J (2020) 'Structure and dynamics of the active Gs-coupled human secretin receptor.' Nature Communications, 11 (1). ISSN 2041-1723

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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.

Item Type: Article
Uncontrolled Keywords: Cryoelectron microscopy, Gastroenterology, Structural biology
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Elements
Date Deposited: 01 Oct 2020 10:31
Last Modified: 13 Nov 2020 22:15
URI: http://repository.essex.ac.uk/id/eprint/28822

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