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首页> 外文期刊>Journal of Molecular Biology >Crystal structures of MMP-9 complexes with five inhibitors: Contribution of the flexible arg424 side-chain to selectivity
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Crystal structures of MMP-9 complexes with five inhibitors: Contribution of the flexible arg424 side-chain to selectivity

机译：具有五种抑制剂的MMP-9配合物的晶体结构：柔性arg424侧链对选择性的贡献

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Human matrix metalloproteinase 9 (MMP-9), also called gelatinase B, is particularly involved in inflammatory processes, bone remodelling and wound healing, but is also implicated in pathological processes such as rheumatoid arthritis, atherosclerosis, tumour growth, and metastasis. We have prepared the inactive E402Q mutant of the truncated catalytic domain of human MMP-9 and co-crystallized it with active site-directed synthetic inhibitors of different binding types. Here, we present the X-ray structures of five MMP-9 complexes with gelatinase-specific, tight binding inhibitors: a phosphinic acid (AM-409), a pyrimidine-2,4,6-trione (RO-206-0222), two carboxylate (An-1 and MJ-24), and a trifluoromethyl hydroxamic acid inhibitor (MS-560). These compounds bind by making a compromise between optimal coordination of the catalytic zinc, favourable hydrogen bond formation in the active-site cleft, and accommodation of their large hydrophobic P1' groups in the slightly flexible S1 cavity, which exhibits distinct rotational conformations of the Pro421 carbonyl group in each complex. In all these structures, the side-chain of Arg424 located at the bottom of the S1' cavity is not defined in the electron density beyond C-gamma, indicating its mobility. However, we suggest that the mobile Arg424 side-chain partially blocks the S1' cavity, which might explain the weaker binding of most inhibitors with a long P1' side-chain for MMP-9 compared with the closely related MMP-2 (gelatinase A), which exhibits a short threonine side-chain at the equivalent position. These novel structural details should facilitate the design of more selective MMP-9 inhibitors. (c) 2007 Elsevier Ltd. All rights reserved.
机译：人基质金属蛋白酶9（MMP-9），也称为明胶酶B，特别参与炎症过程，骨骼重塑和伤口愈合，但也与类风湿关节炎，动脉粥样硬化，肿瘤生长和转移等病理过程有关。我们已经制备了人MMP-9截短的催化结构域的非活性E402Q突变体，并将其与不同结合类型的活性定点合成抑制剂共结晶。在这里，我们介绍了五个具有明胶酶特异性紧密结合抑制剂的MMP-9复合物的X射线结构：次膦酸（AM-409），嘧啶-2,4,6-三酮（RO-206-0222） ，两种羧酸盐（An-1和MJ-24）和三氟甲基异羟肟酸抑制剂（MS-560）。这些化合物通过在催化锌的最佳配位，在活性位隙中形成有利的氢键以及在略微柔韧的S1腔中容纳其较大的疏水性P1'基团之间进行折衷来进行结合，从而显示出Pro421的独特旋转构象每个配合物中的羰基。在所有这些结构中，位于S1'腔底部的Arg424侧链的电子密度没有超过C-γ，表明其迁移率。但是，我们建议移动的Arg424侧链部分阻断S1'腔，这可能解释了与密切相关的MMP-2（明胶酶A）相比，大多数抑制剂的长P1'侧链对MMP-9的结合较弱），其在同等位置具有短的苏氨酸侧链。这些新颖的结构细节应有助于设计更具选择性的MMP-9抑制剂。 （c）2007 Elsevier Ltd.保留所有权利。

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