Crystal structures of MMP-9 complexes with five inhibitors: Contribution of the flexible arg424 side-chain to selectivity
Crystal structures of MMP-9 complexes with five inhibitors: Contribution of the flexible arg424 side-chain to selectivity
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DOI：
10.1016/j.jmb.2007.05.068
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发表时间：
2007-08-24
影响因子：
5.6
通讯作者：
Goettig, Peter
中科院分区：
文献类型：
--
作者：
Tochowicz, Anna;Maskos, Klaus;Goettig, Peter
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、骨重塑和伤口愈合，但也参与病理过程，例如类风湿性关节炎、动脉粥样硬化、肿瘤生长和转移。我们已经制备了人MMP-9截短催化结构域的失活E402 Q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，我们提出了五个MMP-9复合物的X射线结构与明胶酶特异性，紧密结合抑制剂：膦酸（AM-409），嘧啶-2，4，6-三酮（RO-206-0222），两个羧酸（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、在活性位点裂隙中有利的氢键形成以及在稍微灵活的S1腔中容纳它们的大疏水P1'基团之间进行折衷来结合，所述S1腔在每个络合物中表现出不同的Pro 421羰基的旋转构象。在所有这些结构中，位于S1'腔底部的Arg 424的侧链在C-γ以外的电子密度中没有被限定，这表明其迁移率。然而，我们认为移动的Arg 424侧链部分阻断了S1'腔，这可能解释了与密切相关的MMP-2（明胶酶A）相比，大多数具有长P1'侧链的抑制剂对MMP-9的结合较弱，MMP-2在相同位置处具有短苏氨酸侧链。这些新的结构细节将有助于设计更具选择性的MMP-9抑制剂。(c)2007爱思唯尔有限公司保留所有权利。
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.