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TitleConformational transitions and activation of the adhesion receptor CD97.
Journal, issue, pagesMol Cell, Vol. 84, Issue 3, Page 570-583.e7, Year 2024
Publish dateFeb 1, 2024
AuthorsChunyou Mao / Ru-Jia Zhao / Ying-Jun Dong / Mingxin Gao / Li-Nan Chen / Chao Zhang / Peng Xiao / Jia Guo / Jiao Qin / Dan-Dan Shen / Su-Yu Ji / Shao-Kun Zang / Huibing Zhang / Wei-Wei Wang / Qingya Shen / Jin-Peng Sun / Yan Zhang /
PubMed AbstractAdhesion G protein-coupled receptors (aGPCRs) are evolutionarily ancient receptors involved in a variety of physiological and pathophysiological processes. Modulators of aGPCR, particularly ...Adhesion G protein-coupled receptors (aGPCRs) are evolutionarily ancient receptors involved in a variety of physiological and pathophysiological processes. Modulators of aGPCR, particularly antagonists, hold therapeutic promise for diseases like cancer and immune and neurological disorders. Hindered by the inactive state structural information, our understanding of antagonist development and aGPCR activation faces challenges. Here, we report the cryo-electron microscopy structures of human CD97, a prototypical aGPCR that plays crucial roles in immune system, in its inactive apo and G13-bound fully active states. Compared with other family GPCRs, CD97 adopts a compact inactive conformation with a constrained ligand pocket. Activation induces significant conformational changes for both extracellular and intracellular sides, creating larger cavities for Stachel sequence binding and G13 engagement. Integrated with functional and metadynamics analyses, our study provides significant mechanistic insights into the activation and signaling of aGPCRs, paving the way for future drug discovery efforts.
External linksMol Cell / PubMed:38215752
MethodsEM (single particle)
Resolution2.33 - 4.32 Å
Structure data

EMDB-35514, PDB-8ikj:
Cryo-EM structure of the inactive CD97
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-35516, PDB-8ikl:
Cryo-EM structure of the CD97-G13 complex
Method: EM (single particle) / Resolution: 2.33 Å

EMDB-38938: Cryo-EM structure of the inactive CD97
Method: EM (single particle) / Resolution: 4.32 Å

EMDB-38939: Cryo-EM structure of the inactive CD97
Method: EM (single particle) / Resolution: 2.94 Å

EMDB-38980: Cryo-EM structure of the inactive CD97
Method: EM (single particle) / Resolution: 3.35 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • homo sapiens (human)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / adhension GPCR / CD97 / inactive / G13 / complex

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