Dataset Information

Conformational dynamics of the activated GLP-1 receptor-Gs complex revealed by cross-linking mass spectrometry and integrative modeling

ABSTRACT: Despite revolutionary advancements in GPCR structural biology, our understanding of the complexity of GPCR activation and signaling would not be complete without complementary information on the conformational dynamics. Yet it is particularly challenging to study the dynamics of GPCR complexes with their signaling partners due to their transient nature, short living time, and low stability. Here, by combining cross-linking mass spectrometry with integrative modeling, we establish a new approach to portray the alternative conformational ensemble of an activated GPCR-G protein complex at atomic resolution. The integrative structures generated in our study describe heterogeneous conformations for a high number of potential alternative active states for the GLP-1 receptor-Gs complex, which show marked differences from its cryo-EM structure, especially at the receptor-Gs interface and inside Gs heterotrimer. Alanine-scanning mutagenesis coupled with pharmacological assays validates the functional impact of 24 interface residue contacts only observed in the integrative structures yet absent in the cryo-EM structure. Our study provides a unique framework through integrating spatial connectivity data with structural modeling to characterize the conformational dynamics of GPCR signaling complexes.

ORGANISM(S): Homo Sapiens

SUBMITTER: Wenqing Shui

PROVIDER: PXD039315 | iProX | Sun Jan 08 00:00:00 GMT 2023

REPOSITORIES: iProX

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Publications

Conformational Dynamics of the Activated GLP-1 Receptor-G<sub>s</sub> Complex Revealed by Cross-Linking Mass Spectrometry and Integrative Structure Modeling.

Yuan Shijia S Xia Lisha L Wang Chenxi C Wu Fan F Zhang Bingjie B Pan Chen C Fan Zhiran Z Lei Xiaoguang X Stevens Raymond C RC Sali Andrej A Sun Liping L Shui Wenqing W

ACS central science 20230424 5

Despite advances in characterizing the structures and functions of G protein-coupled receptors (GPCRs), our understanding of GPCR activation and signaling is still limited by the lack of information on conformational dynamics. It is particularly challenging to study the dynamics of GPCR complexes with their signaling partners because of their transient nature and low stability. Here, by combining cross-linking mass spectrometry (CLMS) with integrative structure modeling, we map the conformationa ...[more]

PMID: 37252352

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Dataset Information

Conformational dynamics of the activated GLP-1 receptor-Gs complex revealed by cross-linking mass spectrometry and integrative modeling

Publications

Conformational Dynamics of the Activated GLP-1 Receptor-G<sub>s</sub> Complex Revealed by Cross-Linking Mass Spectrometry and Integrative Structure Modeling.

Similar Datasets

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