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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Solution structure and mutational analysis of pituitary adenylate cyclase-activating polypeptide binding to the extracellular domain of PAC1-R_S
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Solution structure and mutational analysis of pituitary adenylate cyclase-activating polypeptide binding to the extracellular domain of PAC1-R_S

机译：垂体腺苷酸环化酶激活多肽与PAC1-R_S胞外域结合的溶液结构和突变分析

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摘要

The pituitary adenylate cyclase-activating polypeptide (PACAP) receptor is a class Ⅱ G protein-coupled receptor that contributes to many different cellular functions including neurotransmission, neuronal survival, and synaptic plasticity. The solution structure of the potent antagonist PACAP (residues 6'-38') complexed to the N-terminal extracellular (EC) domain of the human splice variant hPAC1-R-short (hPAC1-R_S) was determined by NMR. The PACAP peptide adopts a helical conformation when bound to hPAC1-R_S with a bend at residue A18' and makes extensive hydrophobic and electrostatic interactions along the exposed β-sheet and interconnecting loops of the N-terminal EC domain. Mutagenesis data on both the peptide and the receptor delineate the critical interactions between the C terminus of the peptide and the C terminus of the EC domain that define the high affinity and specificity of hormone binding to hPAC1-R_S. These results present a structural basis for hPAC1-R_S selectivity for PACAP versus the vasoactive intestinal peptide and also differentiate PACAP residues involved in binding to the N-terminal extracellular domain versus other parts of the full-length hPAC1-R_S receptor. The structural, mutational, and binding data are consistent with a model for peptide binding in which the C terminus of the peptide hormone interacts almost exclusively with the N-terminal EC domain, whereas the central region makes contacts to both the N-terminal and other extracellular parts of the receptor, ultimately positioning the N terminus of the peptide to contact the transmembrane region and result in receptor activation.
机译：垂体腺苷酸环化酶激活多肽（PACAP）受体是ⅡG类蛋白偶联受体，其参与许多不同的细胞功能，包括神经传递，神经元存活和突触可塑性。通过NMR确定与人剪接变体hPAC1-R-short（hPAC1-R_S）的N-末端细胞外（EC）结构域复合的有效拮抗剂PACAP（残基6'-38'）的溶液结构。当与残基A18'处的弯曲与hPAC1-R_S结合时，PACAP肽采用螺旋构象，并沿着暴露的β-折叠和N端EC域的互连环进行广泛的疏水和静电相互作用。肽和受体的诱变数据描述了肽的C末端和EC域的C末端之间的关键相互作用，这决定了激素与hPAC1-R_S的高亲和力和特异性。这些结果提供了hPAC1-R_S对PACAP相对于血管活性肠肽的选择性的结构基础，并且还区分了与全长hPAC1-R_S受体的其他部分结合的与N末端细胞外结构域结合的PACAP残基。结构，突变和结合数据与肽结合模型一致，在肽结合模型中，肽激素的C末端几乎仅与N末端EC结构域相互作用，而中心区域则与N末端和其他区域接触受体的胞外部分，最终将肽的N端定位成与跨膜区接触并导致受体激活。

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