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

Maoqing Dong; Giuseppe Deganutti; Sarah J. Piper; Yi Lynn Liang; Maryam Khoshouei; Matthew J. Belousoff; Kaleeckal G. Harikumar; Christopher A. Reynolds; Alisa Glukhova; Sebastian G.B. Furness; Arthur Christopoulos; Radostin Danev; Denise Wootten; Patrick M. Sexton; Laurence J. Miller

doi:10.1038/s41467-020-17791-4

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

Maoqing Dong, Giuseppe Deganutti, Sarah J. Piper, Yi Lynn Liang, Maryam Khoshouei, Matthew J. Belousoff, Kaleeckal G. Harikumar, Christopher A. Reynolds, Alisa Glukhova, Sebastian G.B. Furness, Arthur Christopoulos, Radostin Danev, Denise Wootten, Patrick M. Sexton, Laurence J. Miller

Faculty Research Centre for Sport, Exercise and Life Sciences

Research output: Contribution to journal › Article

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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.

Original language	English
Article number	4137
Number of pages	17
Journal	Nature Communications
Volume	11
DOIs	https://doi.org/10.1038/s41467-020-17791-4
Publication status	Published - 18 Aug 2020

Bibliographical note

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.

Keywords

Cryoelectron microscopy
Gastroenterology
Structural biology

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Dong, M., Deganutti, G., Piper, S. J., Liang, Y. L., Khoshouei, M., Belousoff, M. J., ... Miller, L. J. (2020). Structure and dynamics of the active Gs-coupled human secretin receptor. Nature Communications, 11, [4137]. https://doi.org/10.1038/s41467-020-17791-4

Structure and dynamics of the active Gs-coupled human secretin receptor. / Dong, Maoqing; Deganutti, Giuseppe; Piper, Sarah J.; Liang, Yi Lynn; Khoshouei, Maryam; Belousoff, Matthew J.; Harikumar, Kaleeckal G.; Reynolds, Christopher A.; Glukhova, Alisa; Furness, Sebastian G.B.; Christopoulos, Arthur; Danev, Radostin; Wootten, Denise; Sexton, Patrick M.; Miller, Laurence J.

In: Nature Communications, Vol. 11, 4137, 18.08.2020.

Research output: Contribution to journal › Article

Dong, Maoqing ; Deganutti, Giuseppe ; Piper, Sarah J. ; Liang, Yi Lynn ; Khoshouei, Maryam ; Belousoff, Matthew J. ; Harikumar, Kaleeckal G. ; Reynolds, Christopher A. ; Glukhova, Alisa ; Furness, Sebastian G.B. ; Christopoulos, Arthur ; Danev, Radostin ; Wootten, Denise ; Sexton, Patrick M. ; Miller, Laurence J. / Structure and dynamics of the active Gs-coupled human secretin receptor. In: Nature Communications. 2020 ; Vol. 11.

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