New biochemical insight of conserved water molecules at catalytic and structural Zn2+ ions in human matrix metalloproteinase-I: a study by MD-simulation
New biochemical insight of conserved water molecules at catalytic and structural Zn2+ ions in human matrix metalloproteinase-I: a study by MD-simulation
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DOI：
10.1007/s00894-017-3210-6
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发表时间：
2017-02-01
影响因子：
2.2
通讯作者：
Sekar, K.
中科院分区：
文献类型：
--
作者：
Chakrabarti, Bornali;Bairagya, Hridoy R.;Sekar, K.
人基质金属蛋白酶（matrix metalloproteinase， MMP）-1或胶原酶-1在胚胎发育、组织重塑中起重要作用，并参与关节炎、转移等多种疾病。对hmp -1 x射线结构（PDB Id: 1CGE, 1CGF, 1CGL, 1HFC, 2TCL）的分子动力学模拟研究表明，三个保守水分子（W- h /1, W- i, W- s）与催化锌（Zn-C）配位，一个水分子(W)与结构锌离子（Zn-S）配位。在动力学过程中，还观察到Zn-S中Zn-C周围的配位几何从四面体到八面体，从四面体到三角双锥体的转变。两种锌离子通过水介导的桥(Zn-C-W-H （W-1）…报税表……H-183 -Zn-S)和金属离子周围二次配位区的稳定表明Zn-C存在的可能性。ZnS耦合催化hmmp - 1的机理。本研究不仅揭示了保守水分子在hmp - i中的重要功能作用，还强调了其他非催化残基如S172和D170在催化机制中的作用。本研究的结果可能与保守的水介导的序列残基识别位点的重要性有关。202(RWTNNFREY)210， W（色氨酸）203与锌结合组氨酸的相互作用，它们对锌- c和锌- s之间桥接的水分子的影响，以及特异性hMMP抑制剂的结构设计。
Human matrix metalloproteinase (MMP)-1 or collagenase- 1 plays a significant role in embryonic development, tissue remodeling, and is also involved in several diseases like arthritis, metastasis, etc. Molecular dynamics simulation studies on hMMP-1 X-ray structures (PDB Id. 1CGE, 1CGF, 1CGL, 1HFC, and 2TCL) suggest that the three conserved water molecules (W-H/1, W-I, W-S) are coordinated with catalytic zinc (Zn-C), and one water molecule (W) is associated at structural zinc ion (Zn-S). Transition of the coordination geometry around Zn-C from tetrahedral to octahedral and tetrahedral to trigonal bipyramidal at Zn-S are also observed during the dynamics. Recognition of two zinc ions through water mediated bridges (Zn-C-W-H (W-1) ... W-2 ... H-183 -Zn-S) and stabilization of secondary coordination zone around the metal ions indicates the possibility of Zn-C. ZnS coupled catalytic mechanism in hMMP-I. This study not only reveals a functionally important role of conserved water molecules in hMMP-I but also highlights the involvement of other non catalytic residues, such as S172 and D170 in the catalytic mechanism. The results obtained in this study could be relevant for importance of conserved water mediated recognition site of the sequence residue id. 202(RWTNNFREY)210, interaction of W(tryptophan) 203 to zinc bound histidine, their influence on the water molecules that are involved in bridging between Zn-C and Zn-S, and structure-based design of specific hMMP inhibitors.