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

  • Nat Commun. 2020 Aug 18;11(1):4137. doi: 10.1038/s41467-020-17791-4.
Maoqing Dong  #  1 ,  Giuseppe Deganutti  #  2  3 ,  Sarah J Piper  #  4 ,  Yi-Lynn Liang  #  4 ,  Maryam Khoshouei  #  5  6 ,  Matthew J Belousoff  4 ,  Kaleeckal G Harikumar  1 ,  Christopher A Reynolds  2 ,  Alisa Glukhova  4 ,  Sebastian G B Furness  4 ,  Arthur Christopoulos  4 ,  Radostin Danev  7 ,  Denise Wootten  8 ,  Patrick M Sexton  9 ,  Laurence J Miller  10
Affiliations
  • 1. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ, 85259, USA.
  • 2. School of Biological Sciences, University of Essex, Colchester, CO4 3SQ, UK.
  • 3. Centre for Sport, Exercise and Life Sciences, Faculty of Health and Life Sciences, Alison Gingell Building, Coventry University, CV1 2DS, Coventry, UK.
  • 4. Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
  • 5. Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, 82152, Martinsried, Germany.
  • 6. Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002, Basel, Switzerland.
  • 7. Graduate School of Medicine, University of Tokyo, N415, 7-3-1 Hongo, Bunkyo-ku, 113-0033, Tokyo, Japan.
  • 8. Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. [email protected].
  • 9. Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. [email protected].
  • 10. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ, 85259, USA. [email protected].
  • # Contributed equally.
PMID: 32811827 DOI: 10.1038/s41467-020-17791-4
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.