MMP-26的同源模建及S1'结合袋的结构特点

doi:10.7503/cjcu20130811

高等学校化学学报 ›› 2014, Vol. 35 ›› Issue (5): 1063.doi: 10.7503/cjcu20130811

MMP-26的同源模建及S₁'结合袋的结构特点

涂国刚, 刘超, 廖一静, 熊胜涛, 李少华()

南昌大学药学院药物化学教研室, 南昌 330006

收稿日期:2013-08-22 出版日期:2014-05-10 发布日期:2014-04-03
作者简介:联系人简介: 李少华, 男, 博士, 教授, 主要从事基于靶点的新药研究. E-mail:tugg199@yahoo.com
基金资助:
国家自然科学基金(批准号: 81160383, 81260469)和江西省自然科学基金(批准号: 20122BAB205033, 20132BAB205076) 资助

Homology Modeling and S₁' Binding Pocket Characteristics of MMP-26^†

TU Guogang, LIU Chao, LIAO Yijing, XIONG Shengtao, LI Shaohua^*()

Department of Medicinal Chemistry, School of Pharmaceutical Science, Nanchang University, Nanchang 330006, China

Received:2013-08-22 Online:2014-05-10 Published:2014-04-03
Contact: LI Shaohua E-mail:tugg199@yahoo.com
Supported by:
† Supported by the National Natural Science Foundation of China(Nos.B1160383, 81260469) and the Natural Science Foundation of Jiangxi Province, China(Nos.20122BAB205033, 20132BAB205076)

摘要/Abstract

摘要：

以基质金属蛋白酶-12(MMP-12)的晶体结构为模板, 采用同源模建方法构建了基质金属蛋白酶-26(MMP-26)的三维结构, 并阐明了其S₁'结合袋的结构特点, MMP-26中His233残基插入S₁'结合袋, 限制了S₁'结合袋的深度, 符合中袋MMPs的特点, 因此MMP-26属于中袋MMPs. 在此基础上, 研究了抑制剂GM6001与MMP-26的相互作用模式, 发现GM6001中异羟肟酸结构的羰基氧和羟基氧与催化锌离子发生双齿配位, 符合异羟肟酸类MMPs抑制剂的配位特点.

关键词: 基质金属蛋白酶-26, 同源模建, 分子对接

Abstract:

Human matrix metalloproteinase-26(MMP-26/endometase/matrilysin-2) is a newly identified MMP and its structure has not been reported. With the crystal structure of MMP-12 as structural template, the 3D structure of MMP-26 was built by homology modeling, and S₁' binding pocket characteristics was studied. Residue His233 inserted S₁' binding pocket and limited the depth of the pocket, consistent with the interme-diate size prediction. So MMP-26 belongs to intermediate-pocket MMPs. On the basis of the modeling, the interactions of inhibition GM6001 with MMP-26 were investigated. Carbonyl oxygen and hydroxyl oxygen of hydroxamic acid structure were in bidentate coordinated mode with catalytic zinc ion, which was consistent with the characteristics of hydroxamic acids MMPs inhibitors. This work suggests that molecular modeling is a useful tool to understand structure-activity relationships and provides new insight for rational inhibitor design that may distinguish MMPs with deep versus intermediate S₁' pockets.

Key words: MMP-26, Homology modeling, Molecular docking

中图分类号:

O641

TrendMD:

涂国刚, 刘超, 廖一静, 熊胜涛, 李少华. MMP-26的同源模建及S₁'结合袋的结构特点. 高等学校化学学报, 2014, 35(5): 1063.

TU Guogang, LIU Chao, LIAO Yijing, XIONG Shengtao, LI Shaohua. Homology Modeling and S₁' Binding Pocket Characteristics of MMP-26^†. Chem. J. Chinese Universities, 2014, 35(5): 1063.

图/表 7

Fig.1 Multiple sequence alignment of the MMP-26 catalytic domain with other MMPs^The secondary structure elements were taken from the crystal structure of MMP-1. The residue numbering was based on that of MMP-26. Gaps were indicated by hyphens. The S1' loop region was surrounded by a rectangle: ‘*’, identical residues in all six sequences; ‘:’, similar residues by the definition of CLUSTAL X2.

Fig.2 Ramachandran plot of MMP-26 modeled structure

Fig.3 Profile_3D score of MMP-26 modeled structure

Fig.4 Catalytic domain of MMP-26 constructed by homology modeling

Fig.5 RMSD vs time of the atoms from their initial positions during the 10 ns simulation of MMP-26(a) and GM6001(b)

Fig.6 Total potential energy changes of the system during molecular dynamics simulation

Fig.7 Binding profile of GM6001 and MMP-26^The inhibitor GM6001 is represented as a tube with atoms colored. The residues coordinating the catalytic zinc ion(green sphere) or forming hydrogen bond are represented as sticks. Coordination bonds and hydrogen bonds are represented as yellow dash line.

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MMP-26的同源模建及S₁'结合袋的结构特点

Homology Modeling and S₁' Binding Pocket Characteristics of MMP-26^†

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