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bioRxiv · 10.1101/436212

Molecular basis for high affinity agonist binding in GPCRs

Warne, T.·Edwards, P.·Dore, A.·Leslie, A. G. W.·Tate, C. G.
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Abstract

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 {beta}1-adrenoceptor ({beta}1AR) bound to conformation-specific nanobodies in the presence of agonists of varying efficacy. A direct comparison with structures of {beta}1AR 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.\n\nOne Sentence SummaryHigh affinity agonist binding to G protein-coupled GPCRs results from an increase in the number and strength of protein-ligand interactions.

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Warne, T., Edwards, P., Dore, A., Leslie, A. G. W., Tate, C. G.. 2018-10-05. Molecular basis for high affinity agonist binding in GPCRs. https://doi.org/10.1101/436212

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