Dong Jing, Zhao Hongtao, Zhou Ting, Spiliotopoulos Dimitrios, Rajendran Chitra, Li Xiao-Dan, Huang Danzhi, Caflisch Amedeo
Department of Biochemistry, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Laboratory of Biomolecular Research, Paul Scherrer Institut , 5232 Villigen PSI, Switzerland.
ACS Med Chem Lett. 2014 Sep 29;6(1):79-83. doi: 10.1021/ml500355x. eCollection 2015 Jan 8.
We have solved the crystal structures of the EphA3 tyrosine kinase in complex with nine small-molecule inhibitors, which represent five different chemotypes and three main binding modes, i.e., types I and I1/2 (DFG in) and type II (DFG out). The three structures with type I1/2 inhibitors show that the higher affinity with respect to type I is due to an additional polar group (hydroxyl or pyrazole ring of indazole) which is fully buried and is involved in the same hydrogen bonds as the (urea or amide) linker of the type II inhibitors. Overall, the type I and type II binding modes belong to the lock-and-key and induced fit mechanism, respectively. In the type II binding, the scaffold in contact with the hinge region influences the position of the Phe765 side chain of the DFG motif and the orientation of the Gly-rich loop. The binding mode of Birb796 in the EphA3 kinase does not involve any hydrogen bond with the hinge region, which is different from the Birb796/p38 MAP kinase complex. Our structural analysis emphasizes the importance of accounting for structural plasticity of the ATP binding site in the design of type II inhibitors of tyrosine kinases.
我们解析了与9种小分子抑制剂结合的EphA3酪氨酸激酶的晶体结构，这些抑制剂代表了5种不同的化学类型和3种主要结合模式，即I型和I1/2型（DFG在位）以及II型（DFG不在位）。与I1/2型抑制剂结合的三种结构表明，相对于I型，其更高的亲和力归因于一个额外的极性基团（吲唑的羟基或吡唑环），该基团完全被掩埋，并与II型抑制剂的（脲或酰胺）连接基团形成相同的氢键。总体而言，I型和II型结合模式分别属于锁钥机制和诱导契合机制。在II型结合中，与铰链区接触的支架影响DFG基序的Phe765侧链的位置和富含甘氨酸环的方向。EphA3激酶中Birb796的结合模式不涉及与铰链区的任何氢键，这与Birb796/p38丝裂原活化蛋白激酶复合物不同。我们的结构分析强调了在设计酪氨酸激酶II型抑制剂时考虑ATP结合位点结构可塑性的重要性。
