Crystal structure of avian carboxypeptidase D domain II:: a prototype for the regulatory metallocarboxypeptidase subfamily
Crystal structure of avian carboxypeptidase D domain II:: a prototype for the regulatory metallocarboxypeptidase subfamily
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DOI：
10.1093/emboj/18.21.5817
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发表时间：
1999-11-01
期刊：
影响因子：
11.4
通讯作者：
Coll, M
中科院分区：
文献类型：
--
作者：
Gomis-Rüth, FX;Companys, V;Coll, M
鸭羧肽酶D的结构域II的晶体结构，激素原/前肽加工酶集成在一个三个重复串联在自然系统中，已被解决，构成了一个原型的成员的调节性羧肽酶亚家族。它显示了一个300个残基的N-末端α/β-水解酶亚结构域，与典型的胰腺羧肽酶A具有总体拓扑相似性和关键催化残基的总体一致性。然而，在形成漏斗状进入活性位点的区段中的许多显著插入/缺失解释了对较大蛋白质底物或抑制剂的特异性的差异。该α/β-水解酶亚结构域之后是C-末端80个残基的β-夹心亚结构域，其对于这些调节金属酶是独特的，并且在拓扑学上与甲状腺素运载蛋白和糖结合蛋白相关。这里所描述的结构建立了更好地理解诸如激素原加工的机制的基本原理，并且将使得能够对调节羧肽酶进行建模以及更合理地设计羧肽酶D的抑制剂。
The crystal structure of domain II of duck carboxypeptidase D, a prohormone/propeptide processing enzyme integrated in a three repeat tandem in the natural system, has been solved, constituting a prototype for members of the regulatory metallocarboxypeptidase subfamily. It displays a 300 residue N-terminal alpha/beta-hydrolase subdomain with overall topological similarity to and general coincidence of the key catalytic residues with the archetypal pancreatic carboxypeptidase A. However, numerous significant insertions/deletions in segments forming the funnel-like access to the active site explain differences in specificity towards larger protein substrates or inhibitors, This alpha/beta-hydrolase subdomain is followed by a C-terminal 80 residue beta-sandwich subdomain, unique for these regulatory metalloenzymes and topologically related to transthyretin and sugar-binding proteins. The structure described here establishes the fundamentals for a better understanding of the mechanism ruling events such as prohormone processing and will enable modelling of regulatory carboxypeptidases as well as a more rational design of inhibitors of carboxypeptidase D.