3EHU

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

Summary for 3EHU

• Entry DOI: 10.2210/pdb3ehu/pdb
• Related: 3EHS 3EHT
• Related PRD ID: PRD_900001
• Descriptor: FUSION PROTEIN OF CRFR1 EXTRACELLULAR DOMAIN AND MBP, Corticoliberin, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: g protein-coupled receptor, corticotropin releasing factor, crf, scr fold, mbp fusion, extracellular domain, sugar transport, transport, cell membrane, glycoprotein, membrane, phosphoprotein, receptor, transducer, transmembrane, amidation, cleavage on pair of basic residues, hormone, secreted, membrane protein
• Biological source: Escherichia coli; More
• Total number of polymer chains: 4
• Total formula weight: 111225.17

Authors

Pioszak, A.A.,Xu, H.E. (deposition date: 2008-09-14, release date: 2008-09-30, Last modification date: 2024-11-13)

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 (1.96 Å)