Details

Autor(en) / Beteiligte

• Ma, Shanshan
• Shen, Qingya
• Zhao, Li-Hua
• Mao, Chunyou
• Zhou, X. Edward
• Shen, Dan-Dan
• de Waal, Parker W.
• Bi, Peng
• Li, Chuntao
• Jiang, Yi
• Wang, Ming-Wei
• Sexton, Patrick M.
• Wootten, Denise
• Melcher, Karsten
• Zhang, Yan
• Xu, H. Eric

Titel

Molecular Basis for Hormone Recognition and Activation of Corticotropin-Releasing Factor Receptors

Ist Teil von

• Molecular cell, 2020-02, Vol.77 (3), p.669-680.e4

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• Corticotropin-releasing factor (CRF) and the three related peptides urocortins 1–3 (UCN1–UCN3) are endocrine hormones that control the stress responses by activating CRF1R and CRF2R, two members of class B G-protein-coupled receptors (GPCRs). Here, we present two cryoelectron microscopy (cryo-EM) structures of UCN1-bound CRF1R and CRF2R with the stimulatory G protein. In both structures, UCN1 adopts a single straight helix with its N terminus dipped into the receptor transmembrane bundle. Although the peptide-binding residues in CRF1R and CRF2R are different from other members of class B GPCRs, the residues involved in receptor activation and G protein coupling are conserved. In addition, both structures reveal bound cholesterol molecules to the receptor transmembrane helices. Our structures define the basis of ligand-binding specificity in the CRF receptor-hormone system, establish a common mechanism of class B GPCR activation and G protein coupling, and provide a paradigm for studying membrane protein-lipid interactions for class B GPCRs. [Display omitted] •Two cryo-EM structures of CRF1R and CRF2R bound to UCN1 and Gs heterotrimer•Mechanisms of the N-terminal residues of UCN1 in receptor binding and activation•Comparison with the inactive structure reveals conformational changes upon activation•The important role of cholesterols in GPCR signaling is further established The fully active structures of CRF receptors reveal the basis for peptide-binding specificity, support a universal mechanism of class B GPCR activation, and provide detailed structural information for studying membrane protein-lipid interactions.