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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structure of the N-terminal domain of a type B1 G protein-coupled receptor in complex with a peptide ligand
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Structure of the N-terminal domain of a type B1 G protein-coupled receptor in complex with a peptide ligand

机译：与肽配体复合的B1 G型蛋白偶联受体的N末端结构域

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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 CRF 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-R2β 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 CRF 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.
机译：配体的促肾上腺皮质激素释放因子（CRF）家族及其受体协调内分泌，行为，自主和代谢对压力的反应，并在心血管，胃肠道和其他系统中发挥其他作用。 CRF和相关的尿皮质素的作用由两个受体的激活介导，CRF-R1和CRF-R2属于G蛋白偶联受体的B1家族。 CRF受体第一个细胞外结构域（ECD1）内的短共有重复序列（SCR）包含主要的配体结合位点，并通过其C末端片段对接肽配体，从而将N-末端区段与受体的近膜结构域相互作用以激活受体。在这里，我们介绍了CRF-R2βECD1与肽拮抗剂astressin的复合物的3D NMR结构。在复合物的结构中，astressin的C末端片段形成了两亲性螺旋，其整个疏水面与短共识重复基元相互作用，覆盖了较大的分子间界面。另外，该络合物的特征在于分子间氢键和盐桥。通过使用CRF的Ala扫描分析对全长受体亲和力的影响，可以对这些相互作用进行定量加权。这些结构研究确定了CRF配体特异性和选择性的主要决定因素，并支持受体激活的两步模型。此外，由于建议保留ECD1和配体的折叠，因此该结构可作为整个B1受体家族的配体识别模型。

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