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

• DOI: 10.1016/j.molcel.2020.01.013
• Publication Date: 2020-01-30T15:37:00Z
• Authors: Shanshan Ma; Qingya Shen; Li-Hua Zhao; Chunyou Mao; X. Edward Zhou; Dan-Dan Shen; Parker W. de Waal; Peng Bi; Chuntao Li; Yi Jiang; Ming-Wei Wang; Patrick M. Sexton; Denise Wootten; Karsten Melcher; Yan Zhang; H. Eric Xu
• Keywords: 0301 basic medicine; 03 medical and health sciences; Binding Sites; Corticotropin-Releasing Hormone; GTP-Binding Proteins; Cryoelectron Microscopy; GTP-Binding Protein alpha Subunits, Gs; Humans; Amino Acid Sequence; Peptides; Receptors, Corticotropin-Releasing Hormone; Urocortins

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.