Structure of the N-terminal domain of a type B1 G protein-coupled receptor in complex with a peptide ligand
Structure of the N-terminal domain of a type B1 G protein-coupled receptor in complex with a peptide ligand
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DOI：
10.1073/pnas.0700682104
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发表时间：
2007-03-20
影响因子：
11.1
通讯作者：
Riek, Roland
中科院分区：
文献类型：
--
作者：
Grace, Christy Rani R.;Perrin, Marilyn H.;Riek, Roland
促肾上腺皮质激素释放因子（CRF）配体家族及其受体协调对应激的内分泌、行为、自主神经和代谢反应，并在心血管、胃肠道和其他系统中发挥额外的作用。CRF和相关尿皮质素的作用是通过激活属于G蛋白偶联受体B1家族的两种受体CRF-R1和CRF-R2介导的。CRIF受体的第一胞外结构域（ECD 1）内的短共有重复折叠（SCR）包含主要配体结合位点，并用于通过其C末端区段对接肽配体，从而定位N末端区段以与受体的质膜结构域相互作用以激活受体。在这里，我们提出了3D NMR结构的ECD 1的CRF-R2 β与astressin，肽拮抗剂复合。在复合物的结构中，astressin的C-末端区段形成两亲性螺旋，其整个疏水面与短共识重复基序相互作用，覆盖大的分子间界面。此外，配合物的特征在于分子间氢键和盐桥。这些相互作用的定量加权的全长受体亲和力使用Ala扫描CRF的影响的分析。这些结构研究确定了CRIF配体特异性和选择性的主要决定因素，并支持受体活化的两步模型。此外，由于提出了保守的折叠的ECD 1和配体，这种结构可以作为一个模型的配体识别整个B1受体家族。
The corticotropin releasing factor (CRF) family of ligands and their receptors coordinate endocrine, behavioral, autonomic, and metabolic responses to stress and play additional roles within the cardiovascular, gastrointestinal, and other systems. The actions of CRF and the related urocortins are mediated by activation of two receptors, CRF-R1 and CRF-R2, belonging to the B1 family of G protein-coupled receptors. The short-consensus-repeat fold (SCR) within the first extracellular domain (ECD1) of the CRIF receptor(s) comprises the major ligand binding site and serves to dock a peptide ligand via its C-terminal segment, thus positioning the N-terminal segment to interact with the receptor's juxtamembrane domains to activate the receptor. Here we present the 3D NMR structure of ECD1 of CRF-R2 beta in complex with astressin, a peptide antagonist. In the structure of the complex the C-terminal segment of astressin forms an amphipathic helix, whose entire hydrophobic face interacts with the short-consensus-repeat motif, covering a large intermolecular interface. In addition, the complex is characterized by intermolecular hydrogen bonds and a salt bridge. These interactions are quantitatively weighted by an analysis of the effects on the full-length receptor affinities using an Ala scan of CRF. These structural studies identify the major determinants for CRIF ligand specificity and selectivity and support a two-step model for receptor activation. Furthermore, because of a proposed conservation of the fold for both the ECD1s and ligands, this structure can serve as a model for ligand recognition for the entire B1 receptor family.