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首页> 外文期刊>Journal of Molecular Biology >Activation of the ghrelin receptor is described by a privileged collective motion: a model for constitutive and agonist-induced activation of a sub-class A G-protein coupled receptor (GPCR).
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Activation of the ghrelin receptor is described by a privileged collective motion: a model for constitutive and agonist-induced activation of a sub-class A G-protein coupled receptor (GPCR).

机译：生长激素释放肽受体的激活通过特权集体运动来描述：组成型和激动剂诱导的A类A G蛋白偶联受体（GPCR）激活的模型。

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Three homology models of the human ghrelin receptor (GHS-R1a) have been generated from the available X-ray structures of rhodopsin (RHO model), opsin (OPS model) and beta-2 adrenergic receptor (B2 model). The latter was used as a starting point for combined molecular dynamics simulation (MDS) and full atom normal modes analysis (NMA). A low-frequency normal mode (mode 16) perfectly reproduced the intracellular motions observed between B2 and RHO models; in the opposite direction along the same mode, the generated structures are closer to the OPS model, suggesting a direct link with GHS-R1a activation. This was in agreement with motions of the seven transmembranous segments, increase of the solvent accessibility of the 140-ERY-142 sequence, and flip of the Trp276 (C WLP) residue, some features related to GPCRs activation. According to our model, His280 was proposed to stabilize Trp276 in the active state; this was verified by site-directed mutagenesis and biochemical characterization of the resulting H280A and H280S mutants, which were fully functional but sharing an important decrease of their basal activities. Docking performed with short ghrelin derivatives Gly-Ser-Ser ([octa])-Phe-NH (2) and Gly-Ser-Ser ([octa])-Phe-Leu-NH (2) allowed the identification of a robust position of these peptides in the active site of the receptor. This model was refined by MDS and validated by docking experiments performed on a set of 55 ghrelin receptor ligands based on the 1,2,4- triazole scaffold. Finally, NMA performed on the obtained peptide-receptor complex suggested stabilization of the Trp276 residue and of the whole receptor in the active state, preventing the motion observed along mode 16 computed for the unbound receptor. Our results show that NMA offers a powerful approach to study the conformational diversity and the activation mechanism of GPCRs.
机译：从视紫红质（RHO模型），视蛋白（OPS模型）和β-2肾上腺素能受体（B2模型）的可用X射线结构生成了人生长素释放肽受体（GHS-R1a）的三种同源性模型。后者被用作结合分子动力学模拟（MDS）和全原子正态分析（NMA）的起点。低频正常模式（模式16）完美地再现了B2和RHO模型之间观察到的细胞内运动。在相同模式的相反方向上，生成的结构更接近OPS模型，表明与GHS-R1a激活直接相关。这与七个跨膜区段的运动，140-ERY-142序列的溶剂可及性的增加以及Trp276（C WLP）残基的翻转（与GPCR激活相关的一些特征）一致。根据我们的模型，提出了His280来使Trp276稳定在激活状态。所产生的H280A和H280S突变体的定点诱变和生化特性证实了这一点，这些突变体功能齐全，但基础活性却大大降低。用短生长激素释放肽衍生物Gly-Ser-Ser（[octa]）-Phe-NH（2）和Gly-Ser-Ser（[octa）-Phe-Leu-NH（2）对接进行鉴定这些肽在受体的活性位点。该模型通过MDS进行了完善，并通过对基于1,2,4-三唑支架的55种生长素释放肽受体配体进行的对接实验进行了验证。最后，对获得的肽-受体复合物进行的NMA分析表明，Trp276残基和整个受体均处于活化状态，从而防止了沿模式16观察到的未结合受体的运动。我们的结果表明，NMA提供了一种强大的方法来研究GPCR的构象多样性和激活机制。

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