Interaction of human fibrinogen receptor (GPIIb-Ⅲa) with decorsin  

作　　者：JieYANG Chen-yangZHAN Xian-chiDONG KunYANG Fu-xiangWANG 

机构地区：[1]StateKeyLaboratoryofPharmaceuticalBiotechnology,LifeScienceCollege,NanjingUniversity,Nanjing210093,China

出　　处：《Acta Pharmacologica Sinica》2004年第8期1096-1104,共9页中国药理学报（英文版）

基　　金：ProjectsupportedbytheNationalNaturalScienceFoundationofChina,No30171094andNo30271497.

摘　　要：AIM: To build up the structure of human fibrinogen receptor GPⅡb-Ⅲa, subsequently combined with its antagonist decorsin, and to investigate the interaction between decorsin and its receptor GPⅡb-Ⅲa at the molecular level. METHODS: A three-dimensional (3D) molecular model of human fibrinogen receptor GPⅡb-Ⅲa was generated by InsightⅡ, a distance geometry-based homologous modeling package. The structure of human fibrinogen receptor GPⅡb-Ⅲa was built by the InsightⅡ/Homology module using the corresponding of integrin alpha Vbeta.3 (PDB filecode 1JV2) as the template. Then the primary structures were optimized by energy minimization. Subsequently the structural model was docked with its antagonist decorsin (PDB filecode 1dec). RESULTS: A good substrate receptor interaction model was achieved. The interaction sites with decorsin converge at domain 8 (βA domain of β3 subunit) of GPⅡb-Ⅲa. The direct interatomic contacts were made between 16 GPⅡb/Ⅲa residues and 10 decorsin amino-acid residues. These included van der Waals contacts, electrostatic interaction, hydrogen bond, and salt bridge. Residues in contact were concentrated in four dispersed regions of human GPⅡb-Ⅲa: the RGD reaction motif (118-132 of GPⅢa), the span from 210 to 213 of GPⅢa, Thr182 residue and Asp251 residue of GPIIIa; and they were distributed over five segments of decorsin: Asp10 residue, Asn18 and Lys19 residues, Arg28 residue, RGD motif, and Asp35-Pro36-Tyr37 segment. CONCLUSION: This complex model plays an important role in development and research of some new drugs, especially a new guided fusion-type fibrinogen receptor antagonist.AIM: To build up the structure of human fibrinogen receptor GPⅡb-Ⅲa, subsequently combined with its antagonist decorsin, and to investigate the interaction between decorsin and its receptor GPⅡb-Ⅲa at the molecular level. METHODS: A three-dimensional (3D) molecular model of human fibrinogen receptor GPⅡb-Ⅲa was generated by InsightⅡ, a distance geometry-based homologous modeling package. The structure of human fibrinogen receptor GPⅡb-Ⅲa was built by the InsightⅡ/Homology module using the corresponding of integrin alpha Vbeta.3 (PDB filecode 1JV2) as the template. Then the primary structures were optimized by energy minimization. Subsequently the structural model was docked with its antagonist decorsin (PDB filecode 1dec). RESULTS: A good substrate receptor interaction model was achieved. The interaction sites with decorsin converge at domain 8 (βA domain of β3 subunit) of GPⅡb-Ⅲa. The direct interatomic contacts were made between 16 GPⅡb/Ⅲa residues and 10 decorsin amino-acid residues. These included van der Waals contacts, electrostatic interaction, hydrogen bond, and salt bridge. Residues in contact were concentrated in four dispersed regions of human GPⅡb-Ⅲa: the RGD reaction motif (118-132 of GPⅢa), the span from 210 to 213 of GPⅢa, Thr182 residue and Asp251 residue of GPIIIa; and they were distributed over five segments of decorsin: Asp10 residue, Asn18 and Lys19 residues, Arg28 residue, RGD motif, and Asp35-Pro36-Tyr37 segment. CONCLUSION: This complex model plays an important role in development and research of some new drugs, especially a new guided fusion-type fibrinogen receptor antagonist.

关 键 词：platelet glycoprotein GPIIb-Ⅲa complex decorsin drug design 

分 类 号：R914[医药卫生—药物化学]