Modeling the structural basis of human CCR5 chemokine receptor function: From homology model building and molecular dynamics validation to agonist and antagonist docking

被引：35

作者：

Fano, A.

Ritchie, D. W.

Carrieri, A.

机构：

[1] Univ Bari, Dipartimento Farmaco Chim, I-70125 Bari, Italy

[2] Univ Aberdeen, Dept Comp Sci, Aberdeen AB24 3UE, Scotland

来源：

JOURNAL OF CHEMICAL INFORMATION AND MODELING | 2006年 / 46卷 / 03期

关键词：

D O I：

10.1021/ci050490k

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This article describes the construction and validation of a three-dimensional model of the human CCR5 receptor using a homology-based approach starting from the X-ray structure of the bovine rhodopsin receptor. The reliability of the model is assessed through molecular dynamics and docking simulations using both natural agonists and a synthetic antagonist. Some important structural and functional features of the receptor cavity and the extracellular loops are identified, in agreement with data available from site-directed mutagenesis. The results of this study help to explain the structural basis for the recognition, activation, and inhibition processes of CCR5 and may provide fresh insights for the design of HIV-1 entry blockers.

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页码：1223 / 1235

页数：13

相关论文

共 64 条

[1]

[Anonymous], 1993, NACESS COMPUTER PROG

[2] A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity [J].

Baba, M ;

Nishimura, O ;

Kanzaki, N ;

Okamoto, M ;

Sawada, H ;

Iizawa, Y ;

Shiraishi, M ;

Aramaki, Y ;

Okonogi, K ;

Ogawa, Y ;

Meguro, K ;

Fujino, M .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (10) :5698-5703

[3] The SWISS-PROT protein sequence data bank and its supplement TrEMBL in 1998 [J].

Bairoch, A ;

Apweiler, R .

NUCLEIC ACIDS RESEARCH, 1998, 26 (01) :38-42

[4] The core domain of chemokines binds CCR5 extracellular domains while their amino terminus interacts with the transmembrane helix bundle [J].

Blanpain, C ;

Doranz, BJ ;

Bondue, A ;

Govaerts, C ;

De Leener, A ;

Vassart, G ;

Doms, RW ;

Proudfoot, A ;

Parmentier, M .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (07) :5179-5187

[5] Extracellular cysteines of CCR5 are required for chemokine binding, but dispensable for HIV-1 coreceptor activity [J].

Blanpain, C ;

Lee, B ;

Vakili, J ;

Doranz, BJ ;

Govaerts, C ;

Migeotte, I ;

Sharron, M ;

Dupriez, V ;

Vassart, G ;

Doms, RW ;

Parmentier, M .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (27) :18902-18908

[6] Multiple charged and aromatic residues in CCR5 amino-terminal domain are involved in high affinity binding of both chemokines and HIV-1 Env protein [J].

Blanpain, C ;

Doranz, BJ ;

Vakili, J ;

Rucker, J ;

Govaerts, C ;

Baik, SSW ;

Lorthioir, O ;

Migeotte, I ;

Libert, F ;

Baleux, F ;

Vassart, G ;

Doms, RW ;

Parmentier, M .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (49) :34719-34727

[7]

BURKHARD R, 1995, PROTEIN SCI, V4, P521

[8] Theoretical evidence of a salt bridge disruption as the initiating process for the α1d-adrenergic receptor activation:: a molecular dynamics and docking study [J].

Carrieri, A ;

Centeno, NB ;

Rodrigo, J ;

Sanz, F ;

Carotti, A .

PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 2001, 43 (04) :382-394

[9] Substitutions in a homologous region of extracellular loop 2 of CXCR4 and CCR5 alter coreceptor activities for HIV-1 membrane fusion and virus entry [J].

Chabot, DJ ;

Broder, CC .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (31) :23774-23782

[10] IDENTIFICATION OF RANTES, MIP-1-ALPHA, AND MIP-1-BETA AS THE MAJOR HIV-SUPPRESSIVE FACTORS PRODUCED BY CD8(+) T-CELLS [J].

COCCHI, F ;

DEVICO, AL ;

GARZINODEMO, A ;

ARYA, SK ;

GALLO, RC ;

LUSSO, P .

SCIENCE, 1995, 270 (5243) :1811-1815

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