Structures of Human DPP7 Reveal the Molecular Basis of Specific Inhibition and the Architectural Diversity of Proline-Specific Peptidases
Structures of Human DPP7 Reveal the Molecular Basis of Specific Inhibition and the Architectural Diversity of Proline-Specific Peptidases
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DOI：
10.1371/journal.pone.0043019
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发表时间：
2012-08-29
期刊：
影响因子：
3.7
通讯作者：
Dhe-Paganon, Sirano
中科院分区：
文献类型：
--
作者：
Bezerra, Gustavo Arruda;Dobrovetsky, Elena;Dhe-Paganon, Sirano
脯氨酸特异性二肽基肽酶（DPP）是药物开发的新兴靶点。DPP 4抑制剂在许多国家获得批准，其他二肽基肽酶通常被称为DPP 4活性和/或结构同源物（DASH）。DASH家族的成员具有重叠的底物特异性，并且即使它们具有低序列同一性，治疗或临床交叉反应性也是一个问题。在这里，我们报告的结构的人DPP 7及其复合物与选择性抑制剂Dab-Pip（L-2，4-二氨基丁酰-哌啶酰胺），并比较它与DPP 4。这两种酶有一个共同的催化结构域（α/β-水解酶）。催化口袋位于DPP 7的内部，在两个结构域之间的裂缝深处。基底可以通过狭窄的隧道进入活性位点。DPP 7催化三联体是完全保守的，并且包括Ser 162、Asp 418和His 443（对应于DPP 4中的Ser 630、Asp 708和His 740），而衬在催化口袋中的其他残基显著不同。“特异性结构域”在结构上也完全不同，与DPP 7中罕见的完全螺旋折叠相比，DPP 4中表现出b-螺旋桨折叠。比较DPP 7和DPP 4的结构允许设计特异性抑制剂，从而开发交叉反应性更低的药物。此外，报告的DPP 7结构揭示了一些光的脯氨酰特异性肽酶的进化关系，通过分析其结构域的建筑组织。
Proline-specific dipeptidyl peptidases (DPPs) are emerging targets for drug development. DPP4 inhibitors are approved in many countries, and other dipeptidyl peptidases are often referred to as DPP4 activity-and/or structure-homologues (DASH). Members of the DASH family have overlapping substrate specificities, and, even though they share low sequence identity, therapeutic or clinical cross-reactivity is a concern. Here, we report the structure of human DPP7 and its complex with a selective inhibitor Dab-Pip (L-2,4-diaminobutyryl-piperidinamide) and compare it with that of DPP4. Both enzymes share a common catalytic domain (alpha/beta-hydrolase). The catalytic pocket is located in the interior of DPP7, deep inside the cleft between the two domains. Substrates might access the active site via a narrow tunnel. The DPP7 catalytic triad is completely conserved and comprises Ser162, Asp418 and His443 (corresponding to Ser630, Asp708 and His740 in DPP4), while other residues lining the catalytic pockets differ considerably. The "specificity domains" are structurally also completely different exhibiting a b-propeller fold in DPP4 compared to a rare, completely helical fold in DPP7. Comparing the structures of DPP7 and DPP4 allows the design of specific inhibitors and thus the development of less cross-reactive drugs. Furthermore, the reported DPP7 structures shed some light onto the evolutionary relationship of prolyl-specific peptidases through the analysis of the architectural organization of their domains.