Conformational analysis of the DFG-out kinase motif and biochemical profiling of structurally validated type II inhibitors.
Conformational analysis of the DFG-out kinase motif and biochemical profiling of structurally validated type II inhibitors.
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DOI：
10.1021/jm501603h
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发表时间：
2015-01-08
影响因子：
7.3
通讯作者：
Levy RM
中科院分区：
文献类型：
--
作者：
Vijayan RS;He P;Modi V;Duong-Ly KC;Ma H;Peterson JR;Dunbrack RL Jr;Levy RM
随着时间的推移，人类激酶组的结构覆盖率一直在稳步增加。这些结构为激酶功能的分子基础提供了有价值的见解，也为理解激酶抑制剂的机制提供了基础。PDB中存在大量激酶结构，其中激活环上DFG基序的Asp和Phe交换位置，导致形成新的变构口袋。我们将这些结构称为“经典DFG-out”构象，以便将它们与文献中也被称为DFG-out但不具有完全形成的变构口袋的构象区分开。我们已经完成了近200个小分子抑制剂结合到经典的DFG出构象的结构分析，我们发现，它们被识别的I型和II型抑制剂。相比之下，我们发现，非经典的DFG出构象强烈选择对II型抑制剂，因为这些结构还没有形成足够大的变构口袋，以适应这种类型的结合模式。在这项研究的过程中，我们发现，结构验证的II型抑制剂，可以在PDB中发现，也代表在公开可用的激酶抑制剂的生化分析研究的数量是非常少的。我们已经获得了新的分析结果，通过我们的构象分析确定了几个额外的结构验证的II型抑制剂。尽管II型抑制剂的可用特征分析数据仍远小于I型抑制剂，但两个数据集的比较支持II型抑制剂比I型抑制剂更具选择性的结论。我们评论DFG-in到DFG-out构象重组对选择性的可能贡献。
Structural coverage of the human kinome has been steadily increasing over time. The structures provide valuable insights into the molecular basis of kinase function and also provide a foundation for understanding the mechanisms of kinase inhibitors. There are a large number of kinase structures in the PDB for which the Asp and Phe of the DFG motif on the activation loop swap positions, resulting in the formation of a new allosteric pocket. We refer to these structures as “classical DFG-out” conformations in order to distinguish them from conformations that have also been referred to as DFG-out in the literature but that do not have a fully formed allosteric pocket. We have completed a structural analysis of almost 200 small molecule inhibitors bound to classical DFG-out conformations; we find that they are recognized by both type I and type II inhibitors. In contrast, we find that nonclassical DFG-out conformations strongly select against type II inhibitors because these structures have not formed a large enough allosteric pocket to accommodate this type of binding mode. In the course of this study we discovered that the number of structurally validated type II inhibitors that can be found in the PDB and that are also represented in publicly available biochemical profiling studies of kinase inhibitors is very small. We have obtained new profiling results for several additional structurally validated type II inhibitors identified through our conformational analysis. Although the available profiling data for type II inhibitors is still much smaller than for type I inhibitors, a comparison of the two data sets supports the conclusion that type II inhibitors are more selective than type I. We comment on the possible contribution of the DFG-in to DFG-out conformational reorganization to the selectivity.
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影响因子：
14.9
作者：
UniProt Consortium
通讯作者：
UniProt Consortium
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
2.7
作者：
Chartier M;Chénard T;Barker J;Najmanovich R
通讯作者：
Najmanovich R
影响因子：
14.9
作者：
Chiu YY;Lin CT;Huang JW;Hsu KC;Tseng JH;You SR;Yang JM
通讯作者：
Yang JM
影响因子：
64.8
作者：
HUBBARD, SR;WEI, L;HENDRICKSON, WA
通讯作者：
HENDRICKSON, WA