Structural basis of GPBAR activation and bile acid recognition

Nature. 2020 Nov;587(7834):499-504. doi: 10.1038/s41586-020-2569-1. Epub 2020 Jul 22.

Abstract

The G-protein-coupled bile acid receptor (GPBAR) conveys the cross-membrane signalling of a vast variety of bile acids and is a signalling hub in the liver-bile acid-microbiota-metabolism axis1-3. Here we report the cryo-electron microscopy structures of GPBAR-Gs complexes stabilized by either the high-affinity P3954 or the semisynthesized bile acid derivative INT-7771,3 at 3 Å resolution. These structures revealed a large oval pocket that contains several polar groups positioned to accommodate the amphipathic cholic core of bile acids, a fingerprint of key residues to recognize diverse bile acids in the orthosteric site, a putative second bile acid-binding site with allosteric properties and structural features that contribute to bias properties. Moreover, GPBAR undertakes an atypical mode of activation and G protein coupling that features a different set of key residues connecting the ligand-binding pocket to the Gs-coupling site, and a specific interaction motif that is localized in intracellular loop 3. Overall, our study not only reveals unique structural features of GPBAR that are involved in bile acid recognition and allosteric effects, but also suggests the presence of distinct connecting mechanisms between the ligand-binding pocket and the G-protein-binding site in the G-protein-coupled receptor superfamily.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Bile Acids and Salts / chemistry
  • Bile Acids and Salts / metabolism*
  • Binding Sites / drug effects
  • Cholic Acids / chemistry
  • Cholic Acids / pharmacology
  • Cryoelectron Microscopy*
  • GTP-Binding Protein alpha Subunits, Gs / chemistry
  • GTP-Binding Protein alpha Subunits, Gs / metabolism
  • GTP-Binding Protein alpha Subunits, Gs / ultrastructure
  • Humans
  • Ligands
  • Models, Molecular
  • Protein Binding
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, G-Protein-Coupled / ultrastructure*
  • Substrate Specificity

Substances

  • 6alpha-ethyl-23(S)-methylcholic acid
  • Bile Acids and Salts
  • Cholic Acids
  • GPBAR1 protein, human
  • Ligands
  • Receptors, G-Protein-Coupled
  • GTP-Binding Protein alpha Subunits, Gs