Binding site analysis of full-length α1a adrenergic receptor using homology modeling and molecular docking

被引:37
作者
Pedretti, A [1 ]
Silva, ME [1 ]
Villa, L [1 ]
Vistoli, G [1 ]
机构
[1] Univ Milan, Ist Chim Farmaceut, Fac Pharm, I-20131 Milan, Italy
关键词
alpha(1a); adrenergic receptor; norepinephrine; catecholamines; WB-4101; GPCR proteins; homology modeling; molecular docking;
D O I
10.1016/j.bbrc.2004.04.149
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The recent availability of crystal Structure of bovine rhodopsin offers new Opportunities in order to approach the construction of G protein Coupled receptors. This study focuses the attention on the modeling of full-length alpha(1a) adrenergic receptor (alpha(1a)-AR) due to its biological role and significant implications in pharmacological treatment of benign prostate hyperplasia. This work could be considered made up by two main steps: (a) the construction of full structure of of alpha(1a)-AR, through homology modeling methods; (b) the automated docking of an endogenous agonist, norepinephrine, and of an antagonist, WB-4101, using BioDock program. The obtained results highlight the key residues involved in binding sites of both agonists and antagonists, confirming the mutagenesis data and giving new suggestions for the rational design of selective ligands. (C) 2004 Elsevier Inc. All rights reserved.
引用
收藏
页码:493 / 500
页数:8
相关论文
共 33 条
[1]   An alpha-carbon template for the transmembrane helices in the rhodopsin family of G-protein-coupled receptors [J].
Baldwin, JM ;
Schertler, GFX ;
Unger, VM .
JOURNAL OF MOLECULAR BIOLOGY, 1997, 272 (01) :144-164
[2]   Ligand design for α1 adrenoceptor subtype selective antagonists [J].
Bremner, JB ;
Coban, B ;
Griffith, R ;
Groenewoud, KM ;
Yates, BF .
BIOORGANIC & MEDICINAL CHEMISTRY, 2000, 8 (01) :201-214
[3]   Structure of the DNA binding domains from NFAT, Fos and Jun bound specifically to DNA [J].
Chen, L ;
Glover, JNM ;
Hogan, PG ;
Rao, A ;
Harrison, SC .
NATURE, 1998, 392 (6671) :42-48
[4]   α-adrenoceptor antagonists in the treatment of benign prostatic hyperplasia [J].
Cooper, KL ;
McKiernan, JM ;
Kaplan, SA .
DRUGS, 1999, 57 (01) :9-17
[5]  
Dearden J. C., 1998, Pharmacy and Pharmacology Communications, V4, P89
[6]   The crystallographic model of rhodopsin and its use in studies of other G protein-coupled receptors [J].
Filipek, S ;
Teller, DC ;
Palczewski, K ;
Stenkamp, R .
ANNUAL REVIEW OF BIOPHYSICS AND BIOMOLECULAR STRUCTURE, 2003, 32 :375-397
[7]  
FILIPEK S, 2003, ANNU REV PHYSIOL, V65, P81
[8]   SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling [J].
Guex, N ;
Peitsch, MC .
ELECTROPHORESIS, 1997, 18 (15) :2714-2723
[9]   CLONING, FUNCTIONAL EXPRESSION AND TISSUE DISTRIBUTION OF HUMAN CDNA FOR THE ALPHA(1C)-ADRENERGIC RECEPTOR [J].
HIRASAWA, A ;
HORIE, K ;
TANAKA, T ;
TAKAGAKI, K ;
MURAI, M ;
YANO, J ;
TSUJIMOTO, G .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1993, 195 (02) :902-909
[10]   The unique nature of the serine interactions for alpha(1)-adrenergic receptor agonist binding and activation [J].
Hwa, J ;
Perez, DM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (11) :6322-6327