Vulpetti Anna, Crivori Patrizia, Cameron Alexander, Bertrand Jay, Brasca Maria Gabriella, D'Alessio Roberto, Pevarello Paolo
Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
J Chem Inf Model. 2005 Sep-Oct;45(5):1282-90. doi: 10.1021/ci0500280.
An evaluation and comparison of two different approaches, GRID/CPCA and GRIND/CPCA (CPCA = consensus principal component analysis; GRIND = GRid-INdependent Descriptors), suitable for visualizing the structural differences between related proteins is presented. Ten crystal structures of CDK2/cyclin A and GSK3beta solved in-house with different inhibitors were compared with the aim of highlighting regions that could be potential sites for gaining selectivity for CDK2 versus GSK3beta. The analyses pointed out remarkable differences in the backs of the CDK2-GSK3beta ATP binding pockets that guided the optimization toward a selective benzodipyrazole CDK2 inhibitor. The gain in selectivity can be associated with the two main differences in the ATP pocket between the enzymes. Phe80 of CDK2, the so-called gatekeeper residue often exploited for the design of kinase selective ligands, is replaced by a leucine in GSK3beta, and Ala144 is replaced by a cysteine. As a consequence of these mutations, CDK2 has a less elongated and less flat buried region at the back of the ATP pocket.
本文介绍了两种不同方法GRID/CPCA和GRIND/CPCA（CPCA = 一致性主成分分析；GRIND = 网格独立描述符）的评估与比较，这两种方法适用于可视化相关蛋白质之间的结构差异。将内部解析的具有不同抑制剂的CDK2/细胞周期蛋白A和GSK3β的十个晶体结构进行比较，目的是突出那些可能成为对CDK2相对于GSK3β具有选择性的潜在位点的区域。分析指出，CDK2 - GSK3β ATP结合口袋后部存在显著差异，这为向选择性苯并二吡唑CDK2抑制剂的优化提供了指导。选择性的提高可能与这两种酶在ATP口袋中的两个主要差异有关。CDK2的Phe80（即所谓的守门人残基，常用于激酶选择性配体的设计）在GSK3β中被亮氨酸取代，Ala144被半胱氨酸取代。由于这些突变，CDK2在ATP口袋后部的埋藏区域不那么细长且不那么扁平。
