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Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors

Nature volume 401, pages 188–193 (1999)Cite this article

Abstract

Histone deacetylases (HDACs) mediate changes in nucleosome conformation and are important in the regulation of gene expression1. HDACs are involved in cell-cycle progression and differentiation, and their deregulation is associated with several cancers2,3. HDAC inhibitors, such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), have anti-tumour effects, as they can inhibit cell growth4,5,6, induce terminal differentiation4,5 and prevent the formation of tumours in mice models7,8, and they are effective in the treatment of promyelocytic leukemia3. Here we describe the structure of the histone deacetylase catalytic core, as revealed by the crystal structure of a homologue from the hyperthermophilic bacterium Aquifex aeolicus, that shares 35.2% identity with human HDAC1 over 375 residues, deacetylates histones in vitro and is inhibited by TSA and SAHA. The deacetylase, deacetylase–TSA and deacetylase–SAHA structures reveal an active site consisting of a tubular pocket, a zinc-binding site and two Asp–His charge-relay systems, and establish the mechanism of HDAC inhibition. The residues that make up the active site and contact the inhibitors are conserved across the HDAC family. These structures also suggest a mechanism for the deacetylation reaction and provide a framework for the further development of HDAC inhibitors as anti-tumour agents.

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Figure 1: The A. aeolicus HDLP has 35.2% identity to human HDAC1.
Figure 2: The histone deacetylase catalytic core belongs to the open α/β-family of folds.
Figure 3: TSA binds inside the pocket making contacts to residues at the rim, walls and bottom of the pocket.
Figure 4: SAHA binds HDLP like TSA, but its aliphatic chain and cap groups make fewer contacts.
Figure 5: The proposed catalytic mechanism for the deacetylation of acetylated lysine.

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References

  1. Davie,J. R. & Chadee,D. N. Regulation and regulatory parameters of histone modifications. J. Cell Biochem. (Suppl.) 30–31, 203–213 (1998).

    Article  Google Scholar 

  2. Kouzarides,T. Histone acetylases and deacetylases in cell proliferation. Curr. Opin. Genet. Dev. 9, 40–84 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Fenrick,R. & Hiebert,S. W. Role of histone deacetylases in acute leukemia. J. Cell. Biochem. (Suppl.) 30–31, 194–202 (1998).

    Article  Google Scholar 

  4. Yoshida,M., Horinouchi,S. & Beppu,T. Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function. Bioessays 17, 423–430 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Richon,V. M. et al. Second generation hybrid polar compounds are potent inducers of transformed cell differentiation. Proc. Natl Acad. Sci. USA 93, 5705–5708 (1996).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. Richon,V. M. et al. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc. Natl Acad. Sci. USA 95, 3003–3007 (1998).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cohen,L. A. et al. Inhibition of N-methylnitrosourea-induced tumours by the cytodifferentiating agent, suberanilohydroxamic acid (SAHA). Proc. AACR 39, 108, abstr. 736 (1998).

    Google Scholar 

  8. Desai,D., El-Bayoumy,K. & Amin,S. Chemopreventive efficacy of suberanilohydroxamic acid (SAHA), a cytodifferentiating agent, against tobacco-specific nitrosamine 4-(methylinitros-amino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in female A/J mice. Proc. AACR 40, 2396, abstr. 362 (1999).

    Google Scholar 

  9. Struhl,K. Histone acetylation and transcriptional regulatory mechanisms. Genes Dev. 12, 599–606 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Taunton,J. Hassig,C. A. & Schreiber,S. L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272, 408–411 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Grozinger,C. M., Hassig,C. A. & Schreiber,S. L. Three proteins define a class of human histone deacetylases related to yeast Hda1p. Proc. Natl Acad. Sci. USA 96, 4868–4873 (1999).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fischle,W. et al. A new family of human histone deacetylases related to Saccharomyces cerevisiae HDA1p. J. Biol. Chem. 274, 11713–11720 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Leipe,D. D. & Landsman,D. Histone deacetylases, acetoin utilization proteins and acetylpolyamine amidohydrolases are members of an ancient protein superfamily. Nucleic Acids Res. 25, 3693–3697 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hassig,C. A. et al. A role for histone deacetylase activity in HDAC1-mediated transcriptional repression. Proc. Natl Acad. Sci. USA 95, 3519–3524 (1998).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fersht,A. R. & Sperling,J. The charge relay system in chymotrypsin and chymotrypsinogen. J. Mol. Biol. 74, 137–149 (1973).

    Article  CAS  PubMed  Google Scholar 

  16. Chothia,C. & Lesk,A. M. The relation between the divergence of sequence and structure in proteins. EMBO J. 5, 823–826 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Grams,F. et al. Structure determination and analysis of human neutrophil collagenase complexed with a hydroxamate inhibitor. Biochemistry 34, 14012–14020 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. Lovejoy,B. et al. Crystal structures of MMP-1 and -13 reveal the structural basis for selectivity of collagenase inhibitors. Nature Struct. Biol. 6, 217–221 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Holmes,M. A. & Matthews,B. W. Binding of hydroxamic acid inhibitors to crystalline thermolysin suggests a pentacoordinate zinc intermediate in catalysis. Biochemistry 20, 6912–6920 (1981).

    Article  CAS  PubMed  Google Scholar 

  20. Shute,R. E., Dunlap,B. & Rich,D. H. Analogues of the cytostatic and antimitogenic agents chlamydocin and HC-toxin: synthesis and biological activity of chloromethyl ketone and diazomethyl ketone functionalized cyclic tetrapeptides. J. Med. Chem. 30, 71–78 (1987).

    Article  CAS  PubMed  Google Scholar 

  21. Christianson,D. W. & Lipscomb,W. N. Carboxypeptidase A. Acc. Chem. Res. 22, 62–69 (1989).

    Article  CAS  Google Scholar 

  22. Kadosh,D. & Struhl,K. Histone deacetylase activity of Rpd3 is important for transcriptional repression in vivo. Genes Dev. 12, 797–805 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. The CCP4 suite: Programs for computational crystallography. Acta Crystallogr. D 50, 760–763 (1994).

    Article  Google Scholar 

  24. Jones,T. A., Zou,J. Y., Cowan,S. W. & Kjeldgaard,M. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr. A 47, 110–119 (1991).

    Article  PubMed  Google Scholar 

  25. Brunger,A. T. et al. Crystallography and NMR system: A new software suite for macromolecular structure determination. Acta Crystallgr. D 54, 905–921 (1998).

    Article  CAS  Google Scholar 

  26. Hendzel,M. J., Delcuve,G. P. & Davie,J. R. Histone deacetylase is a component of the internal nuclear matrix. J. Biol. Chem. 266, 21936–21942 (1991).

    CAS  PubMed  Google Scholar 

  27. Deckert,G. et al. The complete genome of the hyperthermophilic bacterium Aquifex aeolicus. Nature 392, 353–358 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  28. Kraulis,P. Molscript: A program to produce both detailed and schematic plots of protein structures. J. Appl. Crystallogr. 24, 946–950 (1991).

    Article  Google Scholar 

  29. Merritt,E. A. & Bacon,D. J. Raster3D-Photorealistic molecular graphics. Methods Enzymol. 277, 505–524 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Kanyo,Z. F., Scholnick,L. R., Ash,D. E. & Christianson,D. W. Structure of a unique binuclear manganes cluster in arginase. Nature 383, 554–557 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank R. Huber for the A. aeolicus chromosomal DNA preparation; C. A. Hassig and S. L. Schreiber for the HDAC1-FLAG baculovirus and for helpful discussions; A. S. Mildvan and J. Thornson for advice on the reaction mechanism; and C. Murray for administrative help. Supported by the Howard Hughes Medical Institute, the NIH, the Dewitt Wallace Foundation and the Samuel and May Rudin Foundation.

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Authors and Affiliations

  1. Cellular Biochemistry and Biophsyics Program,

    Jill R. Donigian & Alona Cohen

  2. Howard Hughes Medical Institute, New York, 10021, New York, USA

    Michael S. Finnin & Nikola P. Pavletich

  3. Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Victoria M. Richon, Richard A. Rifkind & Paul A. Marks

  4. Department of Chemistry, Columbia University, New York, 10027, New York, USA

    Ronald Breslow

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Correspondence to Nikola P. Pavletich.

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Finnin, M., Donigian, J., Cohen, A. et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401, 188–193 (1999). https://doi.org/10.1038/43710

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