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

  • Mol Cell. 2020 Feb 6;77(3):669-680.e4. doi: 10.1016/j.molcel.2020.01.013.
Shanshan Ma  1 ,  Qingya Shen  2 ,  Li-Hua Zhao  3 ,  Chunyou Mao  2 ,  X Edward Zhou  4 ,  Dan-Dan Shen  2 ,  Parker W de Waal  4 ,  Peng Bi  2 ,  Chuntao Li  2 ,  Yi Jiang  5 ,  Ming-Wei Wang  6 ,  Patrick M Sexton  7 ,  Denise Wootten  7 ,  Karsten Melcher  4 ,  Yan Zhang  8 ,  H Eric Xu  9
Affiliations
  • 1. The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2. Department of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 3. The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: [email protected].
  • 4. Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute, Grand Rapids, MI, USA.
  • 5. The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 6. The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 7. Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052 VIC, Australia.
  • 8. Department of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: [email protected].
  • 9. The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
PMID: 32004470 DOI: 10.1016/j.molcel.2020.01.013
Abstract

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.