3D MODELING AND CHARACTERIZATION OF HDAC9


Lalit R. Samant, Vikrant C. Sangar, Madhura Khanzode, Abhay Chowdhary

Abstract


Objective: Histones are the most abundant proteins associated with the eukaryotic DNA. The N-terminal tails of these histones are subjected to modifications primarily by two enzymes namely, Histone acetyl transferases (HATs) and Histone deacetylases (HDACs). HDACs help in the regulation of the acetylation of histones and the condensation of the chromatin in its sTable form. HDACs are considered as one of the promising targets in cancer biology studies. HDAC9 is a class II member of HDAC family and they are associated with many neurological disorders and a variety of cancers. The 3D structure of this HDAC9(Q9UKV0) was not published. Thus, the aim of this study was to develop and validate the model structure of HDAC9 (Q9UKV0) using bioinformatics tools.

Methods: The Physiochemical characterization was carried out using Ex PASy Prot Param tool, the Functional characterization using Cysteine Recognition Server and HMMTOP Server and Molecular Modeling using I-TASSER. Model Refinement, Validation and verification are carried out using SPDBV, RAMPAGE Server and ERRAT Server respectively.

Result and Conclusion: This3D model of HDAC9 now can be further used to target drug discovery studies related to HDAC9 neurological disorders and a variety of cancers.

 


Keywords


Histone deacetylase, HDAC9, 3D modelling of HDAC9, I-TASSER, RAMPAGE Server, ERRAT Server.

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References


Cress WD, Seto E. Histone deacetylases, transcriptional control, and cancer. J Cell Physiol 2000;184:1-16.

Hagelkruys A, Sawicka A, Rennmayr M, Seiser C. The biology of HDAC in cancer: the nuclear and epigenetic components. Handb Exp Pharmacol 2011;206:13-37.

Ren J, Zhang J, Cai H, Li Y, Zhang Y, Zhang X. HDAC as a therapeutic target for treatment of endometrial cancers. Curr Pharm Des 2013;20:1847-56.

Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst 2000;92:1210-6.

deRuijter AJM, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 2003;370:737-49.

Gregoretti IV, Lee YM, Goodson HV. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J Mol Bio 2004;338:17-31.

Witt O, Deubzer HE, Milde T, Oehme I. HDAC family: what are the cancer relevant targets? Cancer Lett 2009;277:8-21.

Smith KT, Workman JL. Histone deacetylase inhibitors: anticancer compounds. Int J Biochem Cell Biol 2009;41:21-5.

Mahlknecht U, Schnittger S, Will J, Cicek N, Hoelzer D. Chromosomal organization and localization of the human histone deacetylase 9 gene (HDAC9). Biochem Biophys Res Commun 2002;293:182-91.

Zhou X, Marks PA, Rifkind RA, Richon VM. Cloning and characterization of a histone deacetylase, HDAC9. Proc Natl Acad Sci USA 2001;98:10572-7.

Petrie K, Guidez F, Howell L, Healy L, Waxman S, Greaves M, et al. The histone deacetylase 9 gene encodes multiple protein isoforms. J Biol Chem 2003;278:16059-72.

Zhang CL, McKinsey TA, Chang S, Antos CL, Hill JA, Olson EN. Class II Histone Deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 2002;110:479-88.

Tao R, de Zoeten EF, Ozkaynak E, Chen C, Wang L, Porrett PM. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med 2007;13:1299-307.

de Zoeten EF, Wang L, Sai H, Dillmann WH, Hancock WW. Inhibition of HDAC9 increases T regulatory cell function and prevents colitis in mice. Gastroenterol 2010;138:583-94.

Gasteiger E, Hoogland C, Gattiker A, Duvaud S, Wilkins MR, Appel RD. Protein Identification and Analysis Tools on the ExPASy Server. The Proteomics Protocols Handbook; 2005. p. 571-607.

http://www.softberry.com/berry.phtml?topic=cys_rec&group=programs&subgroup=propt. (Last accessed on 16th July 2014, 21:25 hrs).

Tusnady GE, Simon I. Principles governing amino acid composition of integral membrane proteins: application to topology prediction. J Mol Biol 1998;283:489-506.

Zhang Y. I-TASSER server for protein 3D structure prediction. BMC Bioinf 2008;9:40.

Roy A, Kucukural A, Zhang Y. I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc 2010;5:725-38.

Roy A, Yang J, Zhang Y. COFACTOR: an accurate comparative algorithm for structure-based protein function annotation. Nucleic Acids Res 2012;40:471-7.

Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC. UCSF Chimera-a visualization system for exploratory research and analysis. J Comput Chem 2004;25:1605-12.

Guex N, Peitsch MC. SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling. Electrophor 1997;18:2714-23.

Lovell SC, Davis IW, Arendall WB 3rd, de Bakker PI, Word JM, Prisant MG, et al. Structure validation by Calpha geometry: phi, psi and Cbeta deviation. Proteins 2003;50:437-50.

Colovos C, Yeates TO. Verification of protein structures: patterns of non-bonded atomic interactions. Protein Sci 1993;2:1511-9.




About this article

Title

3D MODELING AND CHARACTERIZATION OF HDAC9

Keywords

Histone deacetylase, HDAC9, 3D modelling of HDAC9, I-TASSER, RAMPAGE Server, ERRAT Server.

Date

25-11-2014

Additional Links

Manuscript Submission

Journal

International Journal of Pharmacy and Pharmaceutical Sciences
Vol 7, Issue 1, 2015 Page: 326-331

Online ISSN

0975-1491

Statistics

296 Views | 105 Downloads

Authors & Affiliations

Lalit R. Samant
Systems Biomedicine Division, Haffkine Institute for Training, Research & Testing, Acharya Donde Marg, Parel, Mumbai 400012, India.
India

Vikrant C. Sangar
Department of Virology & Immunology, Haffkine Institute for Training, Research & Testing, Acharya Donde Marg, Parel, Mumbai 400012, India.
India

Madhura Khanzode
Department of Biotechnology and Bioinformatics, Padmashree Dr. D.Y. Patil University, BelapurCBD, Navi Mumbai 400614, India.
India

Abhay Chowdhary
Department of Virology & Immunology, Haffkine Institute for Training, Research & Testing, Acharya Donde Marg, Parel, Mumbai 400012, India.


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