We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Structure and dynamics of the active Gs-coupled human secretin receptor.
- Authors
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.
- 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. The class B secretin GPCR (SecR) has broad physiological effects, with target potential for treatment of metabolic and cardiovascular disease. Here, authors present a cryo-EM structure and biochemical studies of secretin binding to the SecR:Gs complex which show that interactions between peptide and receptor were dynamic.
- Subjects
PEPTIDE receptors; MOLECULAR dynamics; METABOLIC disorders; MULTIVARIATE analysis; G protein coupled receptors; CARDIOVASCULAR diseases
- Publication
Nature Communications, 2020, Vol 11, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-17791-4