RT Journal Article
SR Electronic
T1 Molecular basis for high affinity agonist binding in GPCRs
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 436212
DO 10.1101/436212
A1 Tony Warne
A1 Patricia C. Edwards
A1 Andrew S. Doré
A1 Andrew G. W. Leslie
A1 Christopher G. Tate
YR 2018
UL http://biorxiv.org/content/early/2018/10/05/436212.abstract
AB A characteristic of GPCRs in the G protein-coupled state is that the affinity of the agonist often increases significantly, but the molecular basis for this is unclear. We have determined six active-state structures of the β1-adrenoceptor (β1AR) bound to conformation-specific nanobodies in the presence of agonists of varying efficacy. A direct comparison with structures of β1AR in inactive states bound to the identical ligands showed a 24-42% reduction in the volume of the orthosteric binding site. Potential hydrogen bonds were also shorter, and there was up to a 30% increase in the number of atomic contacts between the receptor and ligand. GPCRs are highly conserved, so these factors will likely be essential in increasing the affinity of a wide range of structurally distinct agonists.One Sentence Summary High affinity agonist binding to G protein-coupled GPCRs results from an increase in the number and strength of protein-ligand interactions.