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. Epub 2020 Jan 30.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Corticotropin-Releasing Hormone
  • Cryoelectron Microscopy / methods
  • GTP-Binding Protein alpha Subunits, Gs / metabolism
  • GTP-Binding Proteins / metabolism
  • Humans
  • Peptides / metabolism
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • Receptors, Corticotropin-Releasing Hormone / ultrastructure*
  • Urocortins / metabolism


  • CRF receptor type 2
  • Peptides
  • Receptors, Corticotropin-Releasing Hormone
  • UCN protein, human
  • Urocortins
  • CRF receptor type 1
  • Corticotropin-Releasing Hormone
  • GTP-Binding Proteins
  • GTP-Binding Protein alpha Subunits, Gs