Structural basis of GPBAR activation and bile acid recognition.

Nature
Fan YangYan Zhang

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-b...Continue Reading

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Citations

Jan 8, 2021·Clinical Reviews in Allergy & Immunology·Mingming ZhaoQianjin Lu
Oct 29, 2020·Nature Communications·Qingpin XiaoCheng Zhang
Mar 1, 2021·Biophysical Journal·Brennica MarlowJens Meiler
May 29, 2021·Biological Chemistry·Christoph G W GertzenLutz Schmitt
May 18, 2021·Computational and Structural Biotechnology Journal·Longying JiangYongheng Chen
May 18, 2021·The Journal of Clinical Investigation·Alyssa SchledwitzJean-Pierre Raufman
Sep 12, 2021·Proceedings of the National Academy of Sciences of the United States of America·Changxiu QuKa Young Chung
Oct 16, 2021·Expert Opinion on Therapeutic Patents·Rachana S Bhimanwar, Amit Mittal

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Methods Mentioned

BETA
amidation
size-exclusion chromatography
pull-down
BRET
ELISA

Software Mentioned

Bsoft
GraphPad Prism
Phyre2
phenix
PyMOL
Visual Molecular Dynamics ( VMD
Chimera
Coot
MotionCor2
CHARMM

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