Mutagenesis studies of the 14 Å internal cavity of histone deacetylase 1: insights toward the acetate-escape hypothesis and selective inhibitor design.
Mutagenesis studies of the 14 Å internal cavity of histone deacetylase 1: insights toward the acetate-escape hypothesis and selective inhibitor design.
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DOI：
10.1021/jm401837e
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发表时间：
2014-02-13
影响因子：
7.3
通讯作者：
Pflum MK
中科院分区：
文献类型：
--
作者：
Wambua MK;Nalawansha DA;Negmeldin AT;Pflum MK
Histone deacetylase (HDAC) proteins are promising targets for cancer treatment, as shown by the approval of two HDAC inhibitors for the treatment of cutaneous T-cell lymphoma. HDAC1 in particular has been linked to cell growth and cell cycle regulation and is therefore an attractive target for anticancer drugs. The HDAC1 active site contains a hydrophobic 11 Å active-site channel, with a 14 Å internal cavity at the bottom of the active site. Several computational and biochemical studies have proposed an acetate-escape hypothesis where the acetate byproduct of the deacetylation reaction escapes via the 14 Å internal cavity. Selective HDAC inhibitors that bind to the 14 Å cavity have also been created. To understand the influence of amino acids lining the HDAC1 14 Å cavity in acetate escape and inhibitor binding, we used mutagenesis coupled with acetate competition assays. The results indicate that amino acids lining the 14 Å cavity are critical for catalytic activity and acetate competition, confirming the role of the cavity in acetate escape. In addition, these mutagenesis studies will aid in HDAC1-inhibitor design that exploits the 14 Å cavity.
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