Homology modeling and molecular dynamics simulations of the glycine receptor ligand binding domain.
Homology modeling and molecular dynamics simulations of the glycine receptor ligand binding domain.
复制标题
甘氨酸受体配体结合域的同源建模和分子动力学模拟。
DOI：
10.1002/prot.21251
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发表时间：
2007
期刊：
影响因子：
2.9
通讯作者：
Kurnikova,Maria
中科院分区：
文献类型：
--
作者：
Speranskiy,Kirill;Cascio,Michael;Kurnikova,Maria
我们提出了一个同源性为基础的模型的同五聚体α 1甘氨酸受体（GlyR）的配体结合结构域（LBD）。该模型是基于多序列比对与其他成员的烟碱配体门控离子通道超家族和两个同源乙酰胆碱结合蛋白（AChBP）从淡水（滞流）和咸水（AChissia californica）蜗牛与已知的高分辨率结构。使用两个已知结构的模板蛋白来模拟靶蛋白的三维结构对于本文中所提出的具有低同源性的序列是特别有利的。通过对实验和已发表的诱变、功能和其他生化研究的关键评价，对最终模型进行了交叉验证。此外，基于Autodock程序的对接模拟，提出了一种在推定结合位点含有士的宁拮抗剂的复合物结构。报道了用模拟退火协议对GlyR的拟议LBD进行的分子动力学（MD）模拟，GlyR在水中的5 ns模拟中是稳定的，以及在全长乙酰胆碱受体（AChR）α亚基的低分辨率冷冻显微镜结构中确定的相应结构域上建模的变形LBD结构。我们的模拟表明，蛋白质单体的β-三明治中心核心在模拟中是相当刚性的，并且能够抵抗水中的变形。Proteins 2007.© 2007 Wiley利斯公司
We present a homology based model of the ligand binding domain (LBD) of the homopentameric alpha1 glycine receptor (GlyR). The model is based on multiple sequence alignment with other members of the nicotinicoid ligand gated ion channel superfamily and two homologous acetylcholine binding proteins (AChBP) from the freshwater (Lymnaea stagnalis) and saltwater (Aplysia californica) snails with known high resolution structure. Using two template proteins with known structure to model three dimensional structure of a target protein is especially advantageous for sequences with low homology as in the case presented in this paper. The final model was cross‐validated by critical evaluation of experimental and published mutagenesis, functional and other biochemical studies. In addition, a complex structure with strychnine antagonist in the putative binding site is proposed based on docking simulation using Autodock program. Molecular dynamics (MD) simulations with simulated annealing protocol are reported on the proposed LBD of GlyR, which is stable in 5 ns simulation in water, as well as for a deformed LBD structure modeled on the corresponding domain determined in low‐resolution cryomicroscopy structure of the alpha subunit of the full‐length acetylcholine receptor (AChR). Our simulations demonstrate that the beta‐sandwich central core of the protein monomer is fairly rigid in the simulations and resistant to deformations in water. Proteins 2007. © 2007 Wiley‐Liss, Inc.