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首页> 美国卫生研究院文献>Biophysical Journal >Characterization of the Structure of RAMP1 by Mutagenesis and Molecular Modeling
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Characterization of the Structure of RAMP1 by Mutagenesis and Molecular Modeling

机译：通过诱变和分子建模表征RAMP1的结构

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摘要

Receptor activity modifying proteins (RAMPs) are a family of single-pass transmembrane proteins that dimerize with G-protein-coupled receptors. They may alter the ligand recognition properties of the receptors (particularly for the calcitonin receptor-like receptor, CLR). Very little structural information is available about RAMPs. Here, an ab initio model has been generated for the extracellular domain of RAMP1. The disulfide bond arrangement (Cys27-Cys82, Cys40-Cys72, and Cys57-Cys104) was determined by site-directed mutagenesis. The secondary structure (α-helices from residues 29–51, 60–80, and 87–100) was established from a consensus of predictive routines. Using these constraints, an assemblage of 25,000 structures was constructed and these were ranked using an all-atom statistical potential. The best 1000 conformations were energy minimized. The lowest scoring model was refined by molecular dynamics simulation. To validate our strategy, the same methods were applied to three proteins of known structure; PDB:1HP8, PDB:1V54 chain H (residues 21–85), and PDB:1T0P. When compared to the crystal structures, the models had root mean-square deviations of 3.8 Å, 4.1 Å, and 4.0 Å, respectively. The model of RAMP1 suggested that Phe93, Tyr100, and Phe101 form a binding interface for CLR, whereas Trp74 and Phe92 may interact with ligands that bind to the CLR/RAMP1 heterodimer.
机译：受体活性修饰蛋白（RAMP）是一类单程跨膜蛋白，可与G蛋白偶联受体二聚。它们可能会改变受体的配体识别特性（尤其是降钙素受体样受体CLR）。关于RAMP的结构信息很少。在这里，已经为RAMP1的胞外域生成了一个从头开始的模型。二硫键的排列方式（Cys 27 -Cys 82 ，Cys 40 -Cys 72 和Cys 通过定点诱变确定57 -Cys 104 。二级结构（来自残基29–51、60–80和87–100的α螺旋）是根据预测程序的共识建立的。利用这些约束条件，构建了25,000个结构的组合，并使用全原子统计势对这些结构进行了排名。最好的1000种构象被最小化了能量。最低得分模型通过分子动力学模拟进行了完善。为了验证我们的策略，将相同的方法应用于三种已知结构的蛋白质。 PDB：1HP8，PDB：1V54链H（残基21-85）和PDB：1T0P。当与晶体结构比较时，模型的均方根偏差分别为3.8，4.1和4.0。 RAMP1模型建议Phe 93 ，Tyr 100 和Phe 101 构成CLR的绑定接口，而Trp 74 < / sup>和Phe 92 可能与结合CLR / RAMP1异二聚体的配体相互作用。

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