Acta Phys. -Chim. Sin. ›› 2011, Vol. 27 ›› Issue (10): 2432-2446.doi: 10.3866/PKU.WHXB20111001

• BIOPHYSICAL CHEMISTRY • Previous Articles     Next Articles

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).

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