Targeting the Gatekeeper MET146 of C-Jun N-Terminal Kinase 3 Induces a Bivalent Halogen/Chalcogen Bond
Targeting the Gatekeeper MET146 of C-Jun N-Terminal Kinase 3 Induces a Bivalent Halogen/Chalcogen Bond
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DOI：
10.1021/jacs.5b07090
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发表时间：
2015-11-25
影响因子：
15
通讯作者：
Boeckler, Frank M.
中科院分区：
文献类型：
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作者：
Lange, Andreas;Guenther, Marcel;Boeckler, Frank M.
我们靶向c-Jun N-末端激酶3（JNK 3）的看门人MET 146，以验证X...的卤素键在分子设计中使用计算，合成，结构和生物物理技术。在设计的一系列氨基嘧啶类抑制剂中，我们意外地遇到了亲和力的平台。与它们的量子力学计算的相互作用能相比，特别是溴和碘不能根据它们的σ空穴的大小达到全电势。相反，看门人残基突变为亮氨酸、丙氨酸或苏氨酸揭示了较重的卤化物可以显著影响人类激酶组的选择性。因此，我们证明，虽然卤素的选择可能并不总是增加亲和力，它仍然可以诱导选择性相关。测定与JNK 3（4X 21）复合的碘衍生物的晶体结构，揭示了由配体和后袋残基MET 115提供的不寻常的二价卤素/硫属元素键。来自太短的卤素键的初始排斥增加MET 146的C-CH 2的柔性，而剩余的残基不能适应被硫族元素键固定。这种效应可用于诱导选择性，因为甲硫氨酸残基的必要组合仅发生在9.3%的人激酶中，而甲硫氨酸是主要的看门人（39%）。
We target the gatekeeper MET 146 of c-Jun N-terminal kinase 3 (JNK3) to exemplify the applicability of X...s halogen bonds in molecular design using computational, synthetic, structural and biophysical techniques. In a designed series of aminopyrimidine-based inhibitors, we unexpectedly encounter a plateau of affinity. Compared to their QM-calculated interaction energies, particularly bromine and iodine fail to reach the full potential according to the size of their sigma-hole. Instead, mutation of the gatekeeper residue into leucine, alanine, or thereonine reveals that the heavier halides can significantly influence selectivity in the human kinome. Thus, we demonstrate that, although the choice of halogen may not always increase affinity, it can still be relevant for inducing selectivity. Determining the crystal structure of the iodine derivative in complex with JNK3 (4X21) reveals an unusual bivalent halogen/chalcogen bond donated by the ligand and the back-pocket residue MET115. Incipient repulsion from the too short halogen bond increase the flexibility of C-epsilon of MET146, whereas the rest of the residue fails to adapt being fixed by the chalcogen bond. This effect can be useful to induce selectivity, as the necessary combination of methionine residues only occurs in 9.3% of human kinases, while methioine is the predominant gatekeeper (39%).