Skip to main content
SpringerLink
Log in
Book cover

Histone Deacetylases: the Biology and Clinical Implication pp 225–240Cite as

Structural Biology of Human Metal-Dependent Histone Deacetylases

  • Chapter
  • First Online:

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 206))

Abstract

Class I, II, and IV histone deacetylases (HDACs) are metal-dependent enzymes involved in a broad and partly unexplored array of biological mechanisms that include epigenetic control of gene expression. The catalytic domain of human classes I and IIa enzymes has been solved in complex with a substrate peptide and inhibitors, which revealed a conserved architecture, uncovered the catalytic mechanism of deacetylation, and outlined a chemical framework for inhibitor design. We will review the different structural elements of metal-dependent HDACs and their contributions to substrate recognition, catalysis, and inhibitor specificity.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Ago T, Liu T, Zhai P, Chen W, Li H, Molkentin JD, Vatner SF, Sadoshima J (2008) A redox-dependent pathway for regulating class II HDACs and cardiac hypertrophy. Cell 133:978–993

    Article  PubMed  CAS  Google Scholar 

  • Bottomley MJ, Lo Surdo P, Di Giovine P, Cirillo A, Scarpelli R, Ferrigno F, Jones P, Neddermann P, De Francesco R, Steinkuhler C, Gallinari P, Carfi A (2008) Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain. J Biol Chem 283:26694–26704

    Article  PubMed  CAS  Google Scholar 

  • Bradner JE, West N, Grachan ML, Greenberg EF, Haggarty SJ, Warnow T, Mazitschek R (2010) Chemical phylogenetics of histone deacetylases. Nat Chem Biol 6:238–243

    Article  PubMed  CAS  Google Scholar 

  • Bressi JC, Jennings AJ, Skene R, Wu Y, Melkus R, De Jong R, O’Connell S, Grimshaw CE, Navre M, Gangloff AR (2010) Exploration of the HDAC2 foot pocket: synthesis and SAR of substituted N-(2-aminophenyl)benzamides. Bioorg Med Chem Lett 20:3142–3145

    Article  PubMed  CAS  Google Scholar 

  • Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325:834–840

    Article  PubMed  CAS  Google Scholar 

  • Dowling DP, Gantt SL, Gattis SG, Fierke CA, Christianson DW (2008) Structural studies of human histone deacetylase 8 and its site-specific variants complexed with substrate and inhibitors. Biochemistry 47:13554–13563

    Article  PubMed  CAS  Google Scholar 

  • Dowling DP, Gattis SG, Fierke CA, Christianson DW (2010) Structures of metal-substituted human histone deacetylase 8 provide mechanistic inferences on biological function. Biochemistry 49:5048–5056

    Article  PubMed  CAS  Google Scholar 

  • Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA, Breslow R, Pavletich NP (1999) Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401:188–193

    Article  PubMed  CAS  Google Scholar 

  • Fischle W, Dequiedt F, Fillion M, Hendzel MJ, Voelter W, Verdin E (2001) Human HDAC7 histone deacetylase activity is associated with HDAC3 in vivo. J Biol Chem 276:35826–35835

    Article  PubMed  CAS  Google Scholar 

  • Fischle W, Dequiedt F, Hendzel MJ, Guenther MG, Lazar MA, Voelter W, Verdin E (2002) Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. Mol Cell 9:45–57

    Article  PubMed  CAS  Google Scholar 

  • Gantt SL, Gattis SG, Fierke CA (2006) Catalytic activity and inhibition of human histone deacetylase 8 is dependent on the identity of the active site metal ion. Biochemistry 45:6170–6178

    Article  PubMed  CAS  Google Scholar 

  • Grams F, Crimmin M, Hinnes L, Huxley P, Pieper M, Tschesche H, Bode W (1995) Structure determination and analysis of human neutrophil collagenase complexed with a hydroxamate inhibitor. Biochemistry 34:14012–14020

    Article  PubMed  CAS  Google Scholar 

  • Gregoretti IV, Lee YM, Goodson HV (2004) Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J Mol Biol 338:17–31

    Article  PubMed  CAS  Google Scholar 

  • Grozinger CM, Schreiber SL (2002) Deacetylase enzymes: biological functions and the use of small-molecule inhibitors. Chem Biol 9:3–16

    Article  PubMed  CAS  Google Scholar 

  • Hildmann C, Wegener D, Riester D, Hempel R, Schober A, Merana J, Giurato L, Guccione S, Nielsen TK, Ficner R, Schwienhorst A (2006) Substrate and inhibitor specificity of class 1 and class 2 histone deacetylases. J Biotechnol 124:258–270

    Article  PubMed  CAS  Google Scholar 

  • Kanyo ZF, Scolnick LR, Ash DE, Christianson DW (1996) Structure of a unique binuclear manganese cluster in arginase. Nature 383:554–557

    Article  PubMed  CAS  Google Scholar 

  • Lahm A, Paolini C, Pallaoro M, Nardi MC, Jones P, Neddermann P, Sambucini S, Bottomley MJ, Lo Surdo P, Carfi A, Koch U, De Francesco R, Steinkuhler C, Gallinari P (2007) Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases. Proc Natl Acad Sci USA 104:17335–17340

    Article  PubMed  CAS  Google Scholar 

  • Lee H, Rezai-Zadeh N, Seto E (2004) Negative regulation of histone deacetylase 8 activity by cyclic AMP-dependent protein kinase A. Mol Cell Biol 24:765–773

    Article  PubMed  CAS  Google Scholar 

  • Marks PA (2010) The clinical development of histone deacetylase inhibitors as targeted anticancer drugs. Expert Opin Investig Drugs 19:1049–1066

    Article  PubMed  CAS  Google Scholar 

  • Miller TA, Witter DJ, Belvedere S (2003) Histone deacetylase inhibitors. J Med Chem 46:5097–5116

    Article  PubMed  CAS  Google Scholar 

  • Nicolas E, Yamada T, Cam HP, Fitzgerald PC, Kobayashi R, Grewal SI (2007) Distinct roles of HDAC complexes in promoter silencing, antisense suppression and DNA damage protection. Nat Struct Mol Biol 14:372–380

    Article  PubMed  CAS  Google Scholar 

  • Nielsen TK, Hildmann C, Dickmanns A, Schwienhorst A, Ficner R (2005) Crystal structure of a bacterial class 2 histone deacetylase homologue. J Mol Biol 354:107–120

    Article  PubMed  CAS  Google Scholar 

  • Sauve AA, Wolberger C, Schramm VL, Boeke JD (2006) The biochemistry of sirtuins. Annu Rev Biochem 75:435–465

    Article  PubMed  CAS  Google Scholar 

  • Schuetz A, Min J, Allali-Hassani A, Schapira M, Shuen M, Loppnau P, Mazitschek R, Kwiatkowski NP, Lewis TA, Maglathin RL, McLean TH, Bochkarev A, Plotnikov AN, Vedadi M, Arrowsmith CH (2008) Human HDAC7 harbors a class IIa histone deacetylase-specific zinc binding motif and cryptic deacetylase activity. J Biol Chem 283:11355–11363

    Article  PubMed  CAS  Google Scholar 

  • Somoza JR, Skene RJ, Katz BA, Mol C, Ho JD, Jennings AJ, Luong C, Arvai A, Buggy JJ, Chi E, Tang J, Sang BC, Verner E, Wynands R, Leahy EM, Dougan DR, Snell G, Navre M, Knuth MW, Swanson RV, McRee DE, Tari LW (2004) Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure 12:1325–1334

    Article  PubMed  CAS  Google Scholar 

  • Vannini A, Volpari C, Filocamo G, Casavola EC, Brunetti M, Renzoni D, Chakravarty P, Paolini C, De Francesco R, Gallinari P, Steinkuhler C, Di Marco S (2004) Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proc Natl Acad Sci USA 101:15064–15069

    Article  PubMed  CAS  Google Scholar 

  • Vannini A, Volpari C, Gallinari P, Jones P, Mattu M, Carfi A, De Francesco R, Steinkuhler C, Di Marco S (2007) Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8-substrate complex. EMBO Rep 8:879–884

    Article  PubMed  CAS  Google Scholar 

  • Verdin E, Dequiedt F, Kasler HG (2003) Class II histone deacetylases: versatile regulators. Trends Genet 19:286–293

    Article  PubMed  CAS  Google Scholar 

  • Wang D, Helquist P, Wiest O (2007) Zinc binding in HDAC inhibitors: a DFT study. J Org Chem 72:5446–5449

    Article  PubMed  CAS  Google Scholar 

  • Xu WS, Parmigiani RB, Marks PA (2007) Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26:5541–5552

    Article  PubMed  CAS  Google Scholar 

  • Yang XJ, Seto E (2003) Collaborative spirit of histone deacetylases in regulating chromatin structure and gene expression. Curr Opin Genet Dev 13:143–153

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Structural Genomics Consortium (SGC). The SGC is a registered charity (number 1097737) that receives funds from the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., Inc., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research, and the Wellcome Trust.

Author information

Authors and Affiliations

  1. Structural Genomics Consortium and Department of Pharmacology and Toxicology, University of Toronto, 101 College street, Toronto, ON, Canada

    Matthieu Schapira

Authors
  1. Matthieu Schapira
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matthieu Schapira .

Editor information

Editors and Affiliations

  1. , Department of Pharmacology, Duke University, Durham, 27710, North Carolina, USA

    Tso-Pang Yao

  2. , Department of Molecular Oncology, H.Lee Moffitt Cancer Center & Research I, Magnolia Drive 12902, Tampa, 33612, Florida, USA

    Edward Seto

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Schapira, M. (2011). Structural Biology of Human Metal-Dependent Histone Deacetylases. In: Yao, TP., Seto, E. (eds) Histone Deacetylases: the Biology and Clinical Implication. Handbook of Experimental Pharmacology, vol 206. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-21631-2_10

Download citation

Publish with us

Policies and ethics

Search

Navigation