物理化学学报 >> 2011, Vol. 27 >> Issue (10): 2432-2446.doi: 10.3866/PKU.WHXB20111001

生物物理化学 上一篇    下一篇

多巴胺第三受体蛋白三维结构及其活性位点氨基酸残基

金毅1, 王悦1, 卞富永1, 史强2, 葛茂发2, 王树3, 张兴康2,徐四川1,2   

  1. 1. 云南大学化学科学与工程学院, 自然资源药物化学教育部重点实验室, 昆明 650091;
    2. 中国科学院化学研究所, 北京分子科学国家实验室, 分子动态与稳态结构国家重点实验室, 北京 100190;
    3. 中国科学院化学研究所有机固体重点实验室, 北京 100190
  • 收稿日期:2011-05-26 修回日期:2011-06-30 发布日期:2011-09-27
  • 通讯作者: 徐四川 E-mail:sichuan@ynu.edu.cn; xusc1@yahoo.com.cn
  • 基金资助:

    中国科学院百人计划, 云南省人才基金(2006PY01-29)及国家自然科学基金(21163024)资助项目

Three-Dimensional Structure of Dopamine 3-Subtype Receptor with the Active Site Residues for the Binding of Dopamine

JIN Yi1, WANG Yue1, BIAN Fu-Yong1, SHI Qiang2, GE Mao-Fa2, WANG Shu3, ZHANG Xing-Kang2, XU Si-Chuan1,2   

  1. 1. Key Laboratory of Education Ministry for Medicinal Chemistry of Natural Resource, College of Chemical Science and Technology, Yunnan University, Kunming 650091, P. R. China;
    2. State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Beijing National Laboratory for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China;
    3. CAS Key Laboratory of Organic Solids, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
  • Received:2011-05-26 Revised:2011-06-30 Published:2011-09-27
  • Contact: XU Si-Chuan E-mail:sichuan@ynu.edu.cn; xusc1@yahoo.com.cn
  • Supported by:

    The project was supported by the One-Hundred-Talents Project of Chinese Academy of Sciences and Academic Talent Foundation of Yunnan Province, China (2006PY01-29), and National Natural Science Foundation of China (21163024).

摘要: 基于牛视紫红质模板蛋白, 同源模建多巴胺第三受体(D3R)蛋白三维结构, 在1-棕榈酰-2-油酰-卵磷脂(POPC)膜-水模型环境, 开展300 ns 分子动力学模拟提炼优化其结构, 取得稳定的D3R 蛋白三维结构(2B08-D3R). 在该蛋白基础上, 采用MP2/6-31G(d,p)方法, 计算多巴胺(Dop)与氨基酸残基相互作用的结合能,确定五个残基(Asp117、Ser208、His272、Phe269和Thr276)为活性位点. 五个活性位点残基分别位于D3R蛋白跨膜螺旋区TM3、TM5和TM6, 组成活性空腔结构. 多巴胺分子以其苯基平面与TM2-TM7包围的圆柱体空腔平行和非共价键结合方式保留在D3R蛋白中, 与D3R蛋白结合能Eb为-97.8 kJ·mol-1. 基于3PBL D3R突变体晶体结构, 构建了另外一个含有多巴胺分子的D3R蛋白结构(Dop-3PBL-D3R), 确定在该蛋白结构中, 多巴胺的活性位点氨基酸是Asp83、His272、Phe269、Phe268和Trp265. 在该蛋白结构中, 多巴胺分子同样以其苯基平面与TM2-TM7包围的圆柱体空腔平行和非共价键方式结合, 与该蛋白相互作用的结合能是-80.5 kJ·mol-1.

关键词: 从头计算, D3R, 3PBL, 活性位点, 分子动力学模拟, 同源模建

Abstract: The dopamine 3-subtype receptor (D3R) is a promising therapeutic target for the development of new drugs. Using rhodopsin as a template protein, we report homology modeling of a complete D3R structure including dopamine (Dop) in an environment of a 1-palmitoyl-2-oleoylsn-glycero-3-phospha-tidylcholine (POPC) explicit lipid bilayer and water. A 300 ns molecular dynamics (MD) simulation was performed to obtain a stable three-dimensional structure for D3R (2B08-D3R) based on five residues (Asp117, His272, Phe269, Ser208, and Thr276), and these were validated as active sites for the binding of dopamine to the D3R protein by the binding energies (Eb) 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 D3R helical regions, respectively, forming an active pocket for the binding of Dop to the D3R 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 D3R protein. The value of Eb between the Dop and D3R protein is -97.8 kJ·mol-1, which explains why dopamine is easily assimilated into the D3R protein and departs from it as a nerve material and a signal transducer. Using the crystal protein structure of mutated D3R (code: 3PBL) we built another D3R protein structure including dopamine (designated Dop-3PBL-D3R) 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-D3R protein with an Eb of -80.5 kJ·mol-1 between them.

Key words: Ab initio, Dopamine 3-subtype receptor, 3PBL, Active site, Molecular dynamics simulation, Homology modeling

MSC2000: 

  • O641