Journal article
Understanding VPAC receptor family peptide binding and selectivity
SJ Piper, G Deganutti, J Lu, P Zhao, YL Liang, Y Lu, MM Fletcher, MA Hossain, A Christopoulos, CA Reynolds, R Danev, PM Sexton, D Wootten
Nature Communications | Published : 2022
Abstract
The vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) receptors are key regulators of neurological processes. Despite recent structural data, a comprehensive understanding of peptide binding and selectivity among different subfamily receptors is lacking. Here, we determine structures of active, Gs-coupled, VIP-VPAC1R, PACAP27-VPAC1R, and PACAP27-PAC1R complexes. Cryo-EM structural analyses and molecular dynamics simulations (MDSs) reveal fewer stable interactions between VPAC1R and VIP than for PACAP27, more extensive dynamics of VIP interaction with extracellular loop 3, and receptor-dependent differences in interactions of conserved N-termin..
View full abstractRelated Projects (1)
Grants
Awarded by National Institutes of Health
Funding Acknowledgements
This work was supported by the National Health and Medical Research Council of Australia (NHMRC) (program grant 1150083, P.M.S./A.C.; Senior Research Fellowship 1155302, D.W.; Senior Principal Research Fellowship 1154434, P.M.S.). R.D. was supported by Takeda Science Foundation 2019 Medical Research Grant and Japan Science and Technology Agency PRESTO (18069571). C.A.R is grateful for a Royal Society Industry Fellowship. This work was supported by the Monash University Ramaciotti Centre for cryo-electron microscopy (negative staining TEM) and the Monash University MASSIVE high-performance computing facility (cryo-EM data processing). The authors would like to thank Yan Zhang, H. Eric Xu and Yi Jiang for providing access to their structural data for VPAC1R<SUP>10</SUP> prior to publication, George Christopoulos and Villy Julita for generating the expression constructs and alanine mutants of the PAC1R and VPAC1R, as well as Rachel M. Johnson and Matthew J. Belousoff for assisting with map andmodel refinements and validation.