PXD039315

PXD039315 is an original dataset announced via ProteomeXchange.

Title	Conformational dynamics of the activated GLP-1 receptor-Gs complex revealed by cross-linking mass spectrometry and integrative modeling
Description	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.
HostingRepository	iProX
AnnounceDate	2023-01-08
AnnouncementXML	Submission_2023-06-06_23:42:45.742.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Shijia Yuan
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-01-08 20:01:14	ID requested
⏵ 1	2023-06-06 23:42:46	announced

Yuan S, Xia L, Wang C, Wu F, Zhang B, Pan C, Fan Z, Lei X, Stevens RC, Sali A, Sun L, Shui W, Complex Revealed by Cross-Linking Mass Spectrometry and Integrative Structure Modeling. ACS Cent Sci, 9(5):992-1007(2023) [pubmed]

submitter keyword: CLMS, complex, structural dynamics

Wenqing Shui
contact affiliation	ShanghaiTech University
contact email	shuiwq@shanghaitech.edu.cn
lab head
Shijia Yuan
contact affiliation	ShanghaiTech University
contact email	yuanshj@shanghaitec.edu.cn
dataset submitter

iProX dataset URI