Author：scbb
Time：2014-08-22 09:26:19
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Histone deacetylases (HDACs) have found intense interest as drug targets for a variety of diseases, but there is disagreement about basic aspects of the inhibition and mechanism of HDACs. In this study, Kai Chen et.al. found whether including the two aspartic acids in the His-Asp charge-relay systems would influence the protonation states of hydroxamate upon binding to the pocket during QM/MM calculation. SAHA prefers a neutral state if not including two aspartic acids (as shown below colored in magenta, left) in the QM region, while it will be deprotonated spontaneously if including the two aspartic acids(right). This could not only explain the disagreements from different calculations, but also indicate the importance of a suitable QM/MM partition during calculation.
On the basis of this observation, the mechanism was also investigated. Besides the reported proton transfer from water to H143, an alternative proton transfer from water to H142 (
1à
2) was discovered, which could help us understand that hydroxamate functions as an intermediate mimic to inhibit the enzyme activity.
This study further our insights into the unique mechanism of HDACs, including the important role of two catalytic dyads and function of the potassium near active site. They also have important implications for the design of novel inhibitors for a number of HDACs such as class IIa HDACs.
You can access it from this link: http://pubs.acs.org/doi/abs/10.1021/ja501548p
