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 () and Laurence J. Miller ()
Additional contact information
Maoqing Dong: Mayo Clinic
Giuseppe Deganutti: University of Essex
Sarah J. Piper: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University
Yi-Lynn Liang: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University
Maryam Khoshouei: Max Planck Institute of Biochemistry
Matthew J. Belousoff: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University
Kaleeckal G. Harikumar: Mayo Clinic
Christopher A. Reynolds: University of Essex
Alisa Glukhova: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University
Sebastian G. B. Furness: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University
Arthur Christopoulos: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University
Radostin Danev: University of Tokyo
Denise Wootten: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University
Patrick M. Sexton: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University
Laurence J. Miller: Mayo Clinic

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (5)

Downloads: (external link)
https://www.nature.com/articles/s41467-020-17791-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17791-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-17791-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().