Structural basis of inhibitor selectivity in MAP kinases
Structural basis of inhibitor selectivity in MAP kinases
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DOI：
10.1016/s0969-2126(98)00113-0
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发表时间：
1998-09-15
期刊：
影响因子：
5.7
通讯作者：
Goldsmith, EJ
中科院分区：
文献类型：
--
作者：
Wang, ZL;Canagarajah, BJ;Goldsmith, EJ
背景：丝裂原激活蛋白（MAP）激酶是参与多种细胞事件的重要信号分子，是干预炎症、癌症和其他疾病的潜在靶标。MAP 激酶 p38 对环境应激有反应，并参与炎症过程中细胞因子的产生。相反，MAP 激酶 ERK2（细胞外信号调节激酶 2）的激活会导致细胞分化或增殖。 ii-炎症剂吡啶基咪唑及其类似物（SB [SmithKline Beecham] 化合物）是 p38 的高效选择性抑制剂，但不是密切相关的 ERK2 或其他丝氨酸/苏氨酸激酶的抑制剂。尽管已知这些化合物可与 ATP 结合位点结合，但对 p38 的抑制特异性的起源尚不清楚。 结果：我们报告了这些 SE 化合物对 p38 而非 ERK2 的卓越选择性的结构基础，这是通过比较晶体学确定的。此外，还提供了关于 olomoucine（更好的 ERK2 抑制剂）选择性起源的结构数据。这里展示了与 p38 复合的四种 SE 化合物以及与 ERK2 复合的一种 SE 化合物和奥洛穆辛的晶体结构。SE 抑制剂结合在活性位点的扩展口袋中，并与 p38 低活性形式的开放结构域结构互补。 ERK2相对封闭的结构域结构能够容纳较小的olomoucine。结论：在这些复合物中观察到的独特的激酶-抑制剂相互作用源于活性位点中的氨基酸替换和远离活性位点的氨基酸替换，这些替换影响了结构域界面的大小。这些结构信息应该有助于设计更好的 MAP 激酶抑制剂来治疗炎症和其他疾病。
Background: The mitogen-activated protein (MAP) kinases are important signaling molecules that participate in diverse cellular events and are potential targets for intervention in inflammation, cancer, and other diseases, The MAP kinase p38 is responsive to environmental stresses and is involved in the production of cytokines during inflammation. In contrast, the activation of the MAP kinase ERK2 (extracellular-signal-regulated kinase 2) leads to cellular differentiation or proliferation. The an ii-inflammatory agent pyridinylimidazole and its analogs (SB [SmithKline Beecham] compounds) are highly potent and selective inhibitors of p38, but not of the closely related ERK2, or other serine/threonine kinases. Although these compounds are known to bind to the ATP-binding site, the origin of the inhibitory specificity toward p38 is not clear,Results: We report the structural basis for the exceptional selectivity of these SE compounds for p38 over ERK2, as determined by comparative crystallography. In addition, structural data on the origin of olomoucine (abetter inhibitor of ERK2) selectivity are presented. The crystal structures of four SE compounds in complex with p38 and of one SE compound and olomoucine in complex with ERK2 are presented here, The SE inhibitors bind in an extended pocket in the active site and are complementary to the open domain structure of the low-activity form of p38. The relatively closed domain structure of ERK2 is able to accommodate the smaller olomoucine.Conclusions: The unique kinase-inhibitor interactions observed in these complexes originate from amino-acid replacements in the active site and replacements distant from the active site that affect the size of the domain interface. This structural information should facilitate the design of better MAP-kinase inhibitors for the treatment of inflammation and other diseases.