Interactions between human glutamate carboxypeptidase II and urea-based inhibitors: structural characterization.
Interactions between human glutamate carboxypeptidase II and urea-based inhibitors: structural characterization.
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DOI：
10.1021/jm800765e
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发表时间：
2008-12-25
影响因子：
7.3
通讯作者：
Lubkowski J
中科院分区：
文献类型：
--
作者：
Barinka C;Byun Y;Dusich CL;Banerjee SR;Chen Y;Castanares M;Kozikowski AP;Mease RC;Pomper MG;Lubkowski J
基于尿素的低分子量谷氨酸羧肽酶II （GCPII）配体在各种神经疾病模型中显示出疗效，并可作为前列腺癌的显像剂。为了进一步加强这类化合物的开发，我们以高分辨率测定了人类GCPII和尿素基抑制剂之间的四种配合物的x射线结构。所有配体在酶的S1 '口袋内都有一个不变的戊二酸酯片段。P1和P1抑制剂位点之间的脲嘧啶键与活性位点Zn12+离子和Tyr552和His553的侧链相互作用。S1口袋内的相互作用主要由抑制剂的P1羧酸基与Arg534、Arg536和Asn519侧链之间的氢键网络定义。重要的是，我们已经确定了S1位点的疏水口袋附件，可以用于基于结构的设计具有更高亲脂性的新型GCPII抑制剂。
Urea-based, low molecular weight ligands of glutamate carboxypeptidase II (GCPII) have demonstrated efficacy in various models of neurological disorders and can serve as imaging agents for prostate cancer. To enhance further development of such compounds, we determined X-ray structures of four complexes between human GCPII and urea-based inhibitors at high resolution. All ligands demonstrate an invariant glutarate moiety within the S1′ pocket of the enzyme. The ureido linkage between P1 and P1′ inhibitor sites interacts with the active-site Zn12+ ion and the side chains of Tyr552 and His553. Interactions within the S1 pocket are defined primarily by a network of hydrogen bonds between the P1 carboxylate group of the inhibitors and the side chains of Arg534, Arg536, and Asn519. Importantly, we have identified a hydrophobic pocket accessory to the S1 site that can be exploited for structure-based design of novel GCPII inhibitors with increased lipophilicity.
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影响因子：
7.3
作者：
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通讯作者：
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