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首页> 外文期刊>The FEBS journal >Structural insight into the evolutionary and pharmacologic homology of glutamate carboxypeptidases II and III
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Structural insight into the evolutionary and pharmacologic homology of glutamate carboxypeptidases II and III

机译：深入了解谷氨酸羧肽酶II和III的进化和药理同源性

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摘要

Glutamate carboxypeptidase III (GCPIII) is a metalloenzyme that belongs to the transferrin receptor/glutamate carboxypeptidase II (GCPII; EC 3.4.17.21) superfamily. GCPIII has been studied mainly because of its evolutionary relationship to GCPII, an enzyme involved in a variety of neuropathologies and malignancies, such as glutamatergic neurotoxicity and prostate cancer. Given the potential functional and pharmacological overlap between GCPIII and GCPII, studies addressing the structural and physiological properties of GCPIII are crucial for obtaining a deeper understanding of the GCPII/GCPIII system. In the present study, we report high-resolution crystal structures of the human GCPIII ectodomain in a 'pseudo-unliganded' state and in a complex with: (a) l-glutamate (a product of hydrolysis); (b) a phosphapeptide transition state mimetic, namely (2S,3'S)-{[(3'-amino-3'-carboxy-propyl)-hydroxyphosphinoyl]methyl}-pentanedioic acid; and (c) quisqualic acid, a glutamate biostere. Our data reveal the overall fold and quaternary arrangement of the GCPIII molecule, define the architecture of the GCPIII substrate-binding cavity, and offer an experimental evidence for the presence of Znpo ions in the bimetallic active site. Furthermore, the structures allow us to detail interactions between the enzyme and its ligands and to characterize the functional flexibility of GCPIII, which is essential for substrate recognition. A comparison of these GCPIII structures with the equivalent GCPII complexes reveals differences in the organization of specificity pockets, in surface charge distribution, and in the occupancy of the co-catalytic zinc sites. The data presented here provide information that should prove to be essential for the structurally-aided design of GCPIII-specific inhibitors and might comprise guidelines for future comparative GCPII/GCPIII studies.
机译：谷氨酸羧肽酶III（GCPIII）是一种金属酶，属于转铁蛋白受体/谷氨酸羧肽酶II（GCPII; EC 3.4.17.21）的超家族。对GCPIII的研究主要是由于其与GCPII的进化关系，GCPII是一种酶，参与多种神经病理学和恶性肿瘤，例如谷氨酸能神经毒性和前列腺癌。鉴于GCPIII和GCPII之间潜在的功能和药理学重叠，针对GCPIII的结构和生理特性的研究对于深入了解GCPII / GCPIII系统至关重要。在本研究中，我们报告了人GCPIII胞外域的高分辨率晶体结构，处于“伪未配体”状态，并与以下物质形成复合物：（a）l-谷氨酸（水解产物）; （b）磷酸肽过渡态模拟物，即（2S，3'S）-{[（（3'-氨基-3'-羧基-丙基）-羟基膦酰基]甲基}-戊二酸; （c）喹尿酸，一种谷氨酸酯。我们的数据揭示了GCPIII分子的整体折叠和四级排列，定义了GCPIII底物结合腔的结构，并为双金属活性位点中Znpo离子的存在提供了实验证据。此外，该结构使我们能够详细描述酶及其配体之间的相互作用，并表征GCPIII的功能灵活性，这对于底物识别至关重要。将这些GCPIII结构与等效的GCPII配合物进行比较，可以发现特异性口袋的组织，表面电荷分布以及共催化锌位点的占据率存在差异。此处提供的数据提供的信息应被证明对GCPIII特异性抑制剂的结构辅助设计必不可少，并且可能包括未来GCPII / GCPIII比较研究的指南。

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