3EHU

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

3EHU の概要

• エントリーDOI: 10.2210/pdb3ehu/pdb
• 関連するPDBエントリー: 3EHS 3EHT
• 関連するBIRD辞書のPRD_ID: PRD_900001
• 分子名称: FUSION PROTEIN OF CRFR1 EXTRACELLULAR DOMAIN AND MBP, Corticoliberin, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, ... (7 entities in total)
• 機能のキーワード: 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
• 由来する生物種: Escherichia coli; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 111225.17

構造登録者

Pioszak, A.A.,Xu, H.E. (登録日: 2008-09-14, 公開日: 2008-09-30, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.96 Å)