3EHS

Crystal structure of the extracellular domain of human corticotropin releasing factor receptor type 1 (CRFR1)

Summary for 3EHS

• Entry DOI: 10.2210/pdb3ehs/pdb
• Related: 3EHT 3EHU
• Related PRD ID: PRD_900001
• Descriptor: fusion protein of CRFR1 extracellular domain and MBP, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose (3 entities in total)
• Functional Keywords: g protein-coupled receptor, corticotropin releasing factor, scr fold, mbp fusion, extracellular domain, sugar transport, transport, cell membrane, glycoprotein, membrane, phosphoprotein, receptor, transducer, transmembrane, membrane protein
• Biological source: Escherichia coli; More
• Total number of polymer chains: 1
• Total formula weight: 52889.44

Authors

Pioszak, A.A.,Xu, H.E. (deposition date: 2008-09-14, release date: 2008-09-30, Last modification date: 2024-10-30)

Primary citation

Pioszak, A.A.,Parker, N.R.,Suino-Powell, K.,Xu, H.E.
Molecular Recognition of Corticotropin-releasing Factor by Its G-protein-coupled Receptor CRFR1.
J.Biol.Chem., 283:32900-32912, 2008

PubMed Abstract: The bimolecular interaction between corticotropin-releasing factor (CRF), a neuropeptide, and its type 1 receptor (CRFR1), a class B G-protein-coupled receptor (GPCR), is crucial for activation of the hypothalamic-pituitary-adrenal axis in response to stress, and has been a target of intense drug design for the treatment of anxiety, depression, and related disorders. As a class B GPCR, CRFR1 contains an N-terminal extracellular domain (ECD) that provides the primary ligand binding determinants. Here we present three crystal structures of the human CRFR1 ECD, one in a ligand-free form and two in distinct CRF-bound states. The CRFR1 ECD adopts the alpha-beta-betaalpha fold observed for other class B GPCR ECDs, but the N-terminal alpha-helix is significantly shorter and does not contact CRF. CRF adopts a continuous alpha-helix that docks in a hydrophobic surface of the ECD that is distinct from the peptide-binding site of other class B GPCRs, thereby providing a basis for the specificity of ligand recognition between CRFR1 and other class B GPCRs. The binding of CRF is accompanied by clamp-like conformational changes of two loops of the receptor that anchor the CRF C terminus, including the C-terminal amide group. These structural studies provide a molecular framework for understanding peptide binding and specificity by the CRF receptors as well as a template for designing potent and selective CRFR1 antagonists for therapeutic applications.

PubMed: 18801728
DOI: 10.1074/jbc.M805749200

Experimental method

X-RAY DIFFRACTION (2.76 Å)