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Issue 16, 2003
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Ab initio study of the binding of Trichostatin A (TSA) in the active site of Histone Deacetylase Like Protein (HDLP)

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Abstract

Histone deacetylase (HDAC) inhibitors have recently attracted considerable interest because of their therapeutic potential for the treatment of cell proliferative diseases. An X-ray structure of a very potent inhibitor, Trichostatin A (TSA), bound to HDLP (an HDAC analogue isolated from Aquifex aeolicus), is available. From this structure, an active site model (322 atoms), relevant for the binding of TSA and structural analogues, has been derived, and TSA has been minimized in this active site at HF 3-21G* level. The resulting conformation is in excellent accordance with the X-ray structure, and indicates a deprotonation of the hydroxamic acid in TSA by His 131. Also, a water molecule was minimized in the active site. In addition to a similar deprotonation, in accordance with a possible catalytic mechanism of HDAC as proposed by Finnin et al. (M. S. Finnin, J. R. Donigian, A. Cohen, V. M. Richon, R. A. Rifkind and P. A. Marks, Nature, 1999, 401, 188–193), a displacement of the resulting OH ion in the active site was observed. Based on these results, the difference in energy of binding between TSA and water was calculated. The resulting value is realistic in respect to experimental binding affinities. Furthermore, the mechanism of action of the His 131–Asp 166 charge relay system was investigated. Although the Asp residue in this motif is known to substantially increase the basicity of the His residue, no proton transfer from His 131 to Asp 166 was observed on binding of TSA or water. However, in the empty protonated active site, this proton transfer does occur.

Graphical abstract: Ab initio study of the binding of Trichostatin A (TSA) in the active site of Histone Deacetylase Like Protein (HDLP)

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Article information


Submitted
01 May 2003
Accepted
30 Jun 2003
First published
15 Jul 2003

Org. Biomol. Chem., 2003,1, 2951-2957
Article type
Paper

Ab initio study of the binding of Trichostatin A (TSA) in the active site of Histone Deacetylase Like Protein (HDLP)

K. Vanommeslaeghe, C. Van Alsenoy, F. De Proft, J. C. Martins, D. Tourwé and P. Geerlings, Org. Biomol. Chem., 2003, 1, 2951
DOI: 10.1039/B304707E

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