Three-Dimensional Structure of Dopamine 3-Subtype Receptor with the Active Site Residues for the Binding of Dopamine
Three-Dimensional Structure of Dopamine 3-Subtype Receptor with the Active Site Residues for the Binding of Dopamine
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具有结合多巴胺的活性位点残基的多巴胺3亚型受体的三维结构
DOI：
10.3866/pku.whxb20111001
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Xu Si-Chuan
中科院分区：
文献类型：
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作者：
Jin Yi;Wang Yue;Bian Fu-Yong;Shi Qiang;Ge Mao-Fa;Wang Shu;Zhang Xing-Kang;Xu Si-Chuan
多巴胺3亚型受体（dopamine 3-subtype receptor, D_3R）是一个很有希望开发新药的治疗靶点。利用视紫红质作为模板蛋白，我们报道了在1-棕榈酰-2-油基-甘油-3-磷脂-酰胆碱（POPC）外显脂质双分子层和水的环境中，包括多巴胺（Dop）在内的完整D_3R结构的同源性建模。通过300 ns分子动力学（MD）模拟，获得了D_3R（2B08-D_3R）基于5个残基（Asp117、His272、Phe269、Ser208和Thr276）的稳定三维结构，并通过MP2/6-31G（d,p）计算Dop与每个残基之间0.6 nm范围内的结合能（E_b），验证了这些是多巴胺与D_3R蛋白结合的活性位点。这5个关键残基分别位于D_3R螺旋区的TM3、TM5和TM6上，形成了Dop与D_3R蛋白结合的活性口袋。Dop的苯基平面平行于TM2-TM7螺旋区与D_3R蛋白非共价结合时形成的圆柱空间。dopp和D_3R蛋白之间的E_b值为-97.8 kJ·mol~(-1)，这解释了多巴胺作为神经物质和信号换能器容易被D_3R蛋白吸收并离开的原因。利用突变的D_3R晶体蛋白结构（编码：3PBL）构建了另一个包含多巴胺的D_3R蛋白结构（命名为Dop-3PBL-D_3R），并鉴定出5个残基（Asp83、His272、Phe269、Phe268和Trp265）作为Dop结合的活性位点。Dop的苯基平面平行于TM2-TM7螺旋区与Dop- 3pbl - d_3r蛋白非共价结合时形成的圆柱空间，两者之间的E_b为-80.5 kJ·mol~（-1）。
The dopamine 3-subtype receptor(D_3R) is a promising therapeutic target for the development of new drugs.Using rhodopsin as a template protein,we report homology modeling of a complete D_3R structure including dopamine(Dop) in an environment of a 1-palmitoyl-2-oleoylsn-glycero-3-phospha-tidyl- choline(POPC) explicit lipid bilayer and water.A 300 ns molecular dynamics(MD) simulation was performed to obtain a stable three-dimensional structure for D_3R(2B08-D_3R) based on five residues (Asp117,His272,Phe269,Ser208,and Thr276),and these were validated as active sites for the binding of dopamine to the D_3R protein by the binding energies(E_b) calculated using MP2/6-31G(d,p) between Dop and each of the residues within 0.6 nm of Dop.The five key residues are locating on TM3,TM5,and TM6 within the D_3R helical regions,respectively,forming an active pocket for the binding of Dop to the D_3R protein.The phenyl plane of Dop is parallel to the cylinder space formed by the TM2-TM7 helical regions when it bonds non-covalently to the D_3R protein.The value of E_b between the Dop and D_3R protein is -97.8 kJ·mol~(-1),which explains why dopamine is easily assimilated into the D_3R protein and departs from it as a nerve material and a signal transducer.Using the crystal protein structure of mutated D_3R(code:3PBL) we built another D_3R protein structure including dopamine(designated Dop-3PBL-D_3R) and identified five residues(Asp83,His272,Phe269,Phe268,and Trp265) as the active sites for the binding of Dop.The phenyl plane of Dop is also parallel to the cylinder space that is formed by the TM2-TM7 helical regions when it binds non-covalently to the Dop-3PBL-D_3R protein with an E_b of -80.5 kJ·mol~(-1) between them.
DOI：
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发表时间：
2007
期刊：
--
影响因子：
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作者：
M. Frisch;G. Trucks;H. Schlegel;G. Scuseria;M. Robb;J. Cheeseman;V. G. Zakrzewski;J. Montgomery
通讯作者：
M. Frisch;G. Trucks;H. Schlegel;G. Scuseria;M. Robb;J. Cheeseman;V. G. Zakrzewski;J. Montgomery