Structure of class B GPCR corticotropin-releasing factor receptor 1.
Hollenstein, Kaspar 1; Kean, James 1; Bortolato, Andrea 1; Cheng, Robert K. Y. 1; Dore, Andrew S. 1; Jazayeri, Ali 1; Cooke, Robert M. 1; Weir, Malcolm 1; Marshall, Fiona H. 1,*
[Article] Nature. 499(7459):438-443, July 25, 2013.

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: 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.

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