Structure of class B GPCR corticotropin-releasing factor receptor 1

Nature. 2013 Jul 25;499(7459):438-43. doi: 10.1038/nature12357. Epub 2013 Jul 17.


Structural analysis of class B G-protein-coupled receptors (GPCRs), cell-surface proteins that respond to peptide hormones, has been restricted to the amino-terminal extracellular domain, thus providing little understanding of the membrane-spanning signal transduction domain. The corticotropin-releasing factor receptor type 1 is a class B receptor which mediates the response to stress and has been considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of the human corticotropin-releasing factor receptor type 1 in complex with the small-molecule antagonist CP-376395. The structure provides detailed insight into the architecture of class B receptors. Atomic details of the interactions of the receptor with the non-peptide ligand that binds deep within the receptor are described. This structure provides a model for all class B GPCRs and may aid in the design of new small-molecule drugs for diseases of brain and metabolism.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Aminopyridines / chemistry
  • Aminopyridines / metabolism
  • Aminopyridines / pharmacology
  • Binding Sites
  • Conserved Sequence
  • Crystallography, X-Ray
  • HEK293 Cells
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors
  • Receptors, Corticotropin-Releasing Hormone / chemistry*
  • Receptors, Corticotropin-Releasing Hormone / classification*
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • Receptors, Dopamine D3 / antagonists & inhibitors
  • Receptors, Dopamine D3 / chemistry
  • Receptors, Dopamine D3 / classification


  • (3,6-dimethyl-2-(2,4,6-trimethylphenoxy)pyridin-4-yl)(1-ethylpropyl)amine
  • Aminopyridines
  • Ligands
  • Receptors, Corticotropin-Releasing Hormone
  • Receptors, Dopamine D3
  • CRF receptor type 1

Associated data

  • PDB/4K5Y