Pochetti Giorgio, Montanari Roberta, Gege Christian, Chevrier Carine, Taveras Arthur G, Mazza Fernando
Istituto di Cristallografia-CNR, Area della Ricerca Roma 1, Via Salaria Km.29,300, I-00016 Monterotondo Stazione, Roma, Italy.
J Med Chem. 2009 Feb 26;52(4):1040-9. doi: 10.1021/jm801166j.
The mode of binding and the activity of the first two non-zinc chelating, potent, and selective inhibitors of human neutrophil collagenase are reported. The crystal structures of the catalytic domain of MMP-8, respectively complexed with each inhibitor, reveals that both ligands are deeply inserted into the primary specificity subsite S(1)', where they induce a similar conformational change of the surrounding loop that is endowed with the main specificity determinants of MMPs. Accord to this rearrangement, both inhibitors remove the floor of the pocket formed by the Y227 side-chain, rendering available an extra binding region never explored before. The present data show that potent and more selective inhibitors can be obtained by developing ligands able to interact with the selectivity regions of the enzyme rather than with the catalytic zinc ion, which is the common feature of all MMP members.
报道了人中性粒细胞胶原酶的前两种非锌螯合、强效且选择性抑制剂的结合模式和活性。分别与每种抑制剂复合的MMP-8催化结构域的晶体结构表明，两种配体都深深插入主要特异性亚位点S(1)'，在那里它们诱导周围环发生类似的构象变化，该环具有MMPs的主要特异性决定因素。根据这种重排，两种抑制剂都去除了由Y227侧链形成的口袋底部，从而提供了一个以前从未探索过的额外结合区域。目前的数据表明，通过开发能够与酶的选择性区域而非催化锌离子相互作用的配体，可以获得强效且更具选择性的抑制剂，这是所有MMP成员的共同特征。
