Conformational dynamics and allosteric effect modulated by the unique zinc-binding motif in class IIa HDACs
Conformational dynamics and allosteric effect modulated by the unique zinc-binding motif in class IIa HDACs
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IIa 类 HDAC 中独特的锌结合基序调节构象动力学和变构效应
DOI：
10.1039/c9cp02261a
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发表时间：
2019
影响因子：
3.3
通讯作者：
Wu Ruibo
中科院分区：
文献类型：
--
作者：
Liu Huawei;Zhang Fan;Wang Kai;Tang Xiaowen;Wu Ruibo
IIa类组蛋白去乙酰化酶（HDAC）已被认为是治疗多种疾病的潜在靶标。与其他HDAC相比，IIa类HDAC具有额外的第二锌结合基序。到目前为止，这个独特的锌结合基序的功能还不是很清楚。在这项工作中，广泛的经典分子动力学（MD）模拟照亮独特的锌结合基序调制的构象变化。已经揭示，独特的锌结合基序是保持酶的催化活性和多蛋白复合物的稳定性的关键结构稳定因子，通过远程调节活性位点口袋中的“闭合”构象。此外，还揭示了HDAC 4中Loop 2运动的灵活性低于HDAC 7，这为利用结构高度相似的HDAC 4和HDAC 7之间的局部构象动力学差异来设计选择性抑制剂开辟了新的途径。最后，通过与I类HDAC（HDAC 1 -3）的比较研究，发现在HDAC 1 -3中自发地发生结合轨道的可逆的“in-out”构象转变（在I类和IIa类HDAC中均高度保守），而在IIa类HDAC中由于独特的CCHC锌结合基序的强金属配位相互作用，结合轨道被捕获在“in”构象中。因此，CCHC锌结合基序可能是开发IIa类选择性抑制剂的可行的变构位点。
Class IIa histone deacetylases (HDACs) have been considered as potential targets for the treatment of several diseases. Compared to other HDACs, class IIa HDACs have an additional second zinc binding motif. So far, the function of the unique zinc-binding motif is still not very clear. In this work, extensive classical molecular dynamics (MD) simulations were employed to illuminate the conformational change modulated by the unique zinc-binding motif. It has been revealed that the unique zinc-binding motif is a crucial structural stabilization factor in retaining the catalytic activity of the enzyme and the stability of the multi-protein complex, by remotely modulating the active site pocket in a “closed” conformation. Moreover, it is also revealed that the Loop2 motion in HDAC4 is less flexible than that in HDAC7, which opens a new avenue to design selective inhibitors by utilizing the local conformational dynamics difference between the structurally highly similar HDAC4 and HDAC7. Finally, by comparative studies with class I HDACs (HDAC1–3), it is found that the reversible “in–out” conformational transformation of the binding rail (highly conserved both in class I and IIa HDACs) occurs spontaneously in HDAC1–3, whereas the binding rail is trapped in an “in” conformation owing to the strong metal coordination interaction of the unique CCHC zinc-binding motif in class IIa HDACs. Thus, the CCHC zinc-binding motif may be a feasible allosteric site for the development of class IIa-selective inhibitors.