This is an unedited manuscript that has been accepted for publication. Nature Research are providing this early version of the manuscript as a service to our authors and readers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

Structural basis of GPBAR activation and bile acid recognition


The G protein-coupled bile acid receptor (GPBAR) conveys the cross-membrane signaling of a vast variety of bile acids and is a signaling hub in the liver–bile-acid–microbiota–metabolism axis1–3. Here, we report the cryo-EM 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-shaped pocket containing 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 contributing to bias properties. Moreover, GPBAR undertakes an atypical mode of activation and G-protein coupling featuring a different set of key residues connecting the ligand binding pocket to the Gs coupling site, and a specific interaction motif localized in intracellular loop 3. Overall, our study not only reveals unique structural features of GPBAR 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 GPCR superfamily.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Author information



Corresponding authors

Correspondence to Jin-Peng Sun or Xin Xie or Xiao Yu or Yan Zhang.

Supplementary information

Supplementary information

This file contains Supplementary Figures 1-5 and Supplementary Tables 1-9.

Reporting Summary

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yang, F., Mao, C., Guo, L. et al. Structural basis of GPBAR activation and bile acid recognition. Nature (2020).

Download citation


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.