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Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity.

Ng SS, Kavanagh KL, McDonough MA, Butler D, Pilka ES, Lienard BM, Bray JE, Savitsky P, Gileadi O, von Delft F, Rose NR, Offer J, Scheinost JC, Borowski T, Sundstrom M, Schofield CJ, Oppermann U
Nature 448 87-91 (2007)
Related entries: 2oq6, 2oq7, 2ot7, 2ox0

Cited: 213 times
EuropePMC logo PMID: 17589501

Abstract

Post-translational histone modification has a fundamental role in chromatin biology and is proposed to constitute a 'histone code' in epigenetic regulation. Differential methylation of histone H3 and H4 lysyl residues regulates processes including heterochromatin formation, X-chromosome inactivation, genome imprinting, DNA repair and transcriptional regulation. The discovery of lysyl demethylases using flavin (amine oxidases) or Fe(II) and 2-oxoglutarate as cofactors (2OG oxygenases) has changed the view of methylation as a stable epigenetic marker. However, little is known about how the demethylases are selective for particular lysyl-containing sequences in specific methylation states, a key to understanding their functions. Here we reveal how human JMJD2A (jumonji domain containing 2A), which is selective towards tri- and dimethylated histone H3 lysyl residues 9 and 36 (H3K9me3/me2 and H3K36me3/me2), discriminates between methylation states and achieves sequence selectivity for H3K9. We report structures of JMJD2A-Ni(II)-Zn(II) inhibitor complexes bound to tri-, di- and monomethyl forms of H3K9 and the trimethyl form of H3K36. The structures reveal a lysyl-binding pocket in which substrates are bound in distinct bent conformations involving the Zn-binding site. We propose a mechanism for achieving methylation state selectivity involving the orientation of the substrate methyl groups towards a ferryl intermediate. The results suggest distinct recognition mechanisms in different demethylase subfamilies and provide a starting point to develop chemical tools for drug discovery and to study and dissect the complexity of reversible histone methylation and its role in chromatin biology.

Reviews - 2os2 mentioned but not cited (6)

  1. Histone lysine methylation dynamics: establishment, regulation, and biological impact. Black JC, Van Rechem C, Whetstine JR. Mol Cell 48 491-507 (2012)
  2. Histone modifying enzymes: structures, mechanisms, and specificities. Marmorstein R, Trievel RC. Biochim Biophys Acta 1789 58-68 (2009)
  3. Structural insights into histone lysine demethylation. Hou H, Yu H. Curr Opin Struct Biol 20 739-748 (2010)
  4. Histone demethylases and cancer. Kampranis SC, Tsichlis PN. Adv Cancer Res 102 103-169 (2009)
  5. Modulation of epigenetic targets for anticancer therapy: clinicopathological relevance, structural data and drug discovery perspectives. Andreoli F, Barbosa AJ, Parenti MD, Del Rio A. Curr Pharm Des 19 578-613 (2013)
  6. Dynamics of histone lysine methylation: structures of methyl writers and erasers. Upadhyay AK, Cheng X. Prog Drug Res 67 107-124 (2011)

Articles - 2os2 mentioned but not cited (7)



Reviews citing this publication (69)

  1. Molecular mechanisms and potential functions of histone demethylases. Kooistra SM, Helin K. Nat Rev Mol Cell Biol 13 297-311 (2012)
  2. Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. Cloos PA, Christensen J, Agger K, Helin K. Genes Dev 22 1115-1140 (2008)
  3. Reversal of histone methylation: biochemical and molecular mechanisms of histone demethylases. Mosammaparast N, Shi Y. Annu Rev Biochem 79 155-179 (2010)
  4. Histone lysine demethylases as targets for anticancer therapy. Højfeldt JW, Agger K, Helin K. Nat Rev Drug Discov 12 917-930 (2013)
  5. KDM4/JMJD2 histone demethylases: epigenetic regulators in cancer cells. Berry WL, Janknecht R. Cancer Res 73 2936-2942 (2013)
  6. Inhibition of 2-oxoglutarate dependent oxygenases. Rose NR, McDonough MA, King ON, Kawamura A, Schofield CJ. Chem Soc Rev 40 4364-4397 (2011)
  7. Chemical mechanisms of histone lysine and arginine modifications. Smith BC, Denu JM. Biochim Biophys Acta 1789 45-57 (2009)
  8. Physiological and biochemical aspects of hydroxylations and demethylations catalyzed by human 2-oxoglutarate oxygenases. Loenarz C, Schofield CJ. Trends Biochem Sci 36 7-18 (2011)
  9. Structural studies on human 2-oxoglutarate dependent oxygenases. McDonough MA, Loenarz C, Chowdhury R, Clifton IJ, Schofield CJ. Curr Opin Struct Biol 20 659-672 (2010)
  10. The redox basis of epigenetic modifications: from mechanisms to functional consequences. Cyr AR, Domann FE. Antioxid Redox Signal 15 551-589 (2011)
  11. Coordinated chromatin control: structural and functional linkage of DNA and histone methylation. Cheng X, Blumenthal RM. Biochemistry 49 2999-3008 (2010)
  12. 2-Oxoglutarate-Dependent Oxygenases. Islam MS, Leissing TM, Chowdhury R, Hopkinson RJ, Schofield CJ. Annu Rev Biochem 87 585-620 (2018)
  13. Chemical biology of protein arginine modifications in epigenetic regulation. Fuhrmann J, Clancy KW, Thompson PR. Chem Rev 115 5413-5461 (2015)
  14. Histone H3 phosphorylation - a versatile chromatin modification for different occasions. Sawicka A, Seiser C. Biochimie 94 2193-2201 (2012)
  15. Targeting histone lysine methylation in cancer. McGrath J, Trojer P. Pharmacol Ther 150 1-22 (2015)
  16. Mechanisms of human histone and nucleic acid demethylases. Walport LJ, Hopkinson RJ, Schofield CJ. Curr Opin Chem Biol 16 525-534 (2012)
  17. The roles of Jumonji-type oxygenases in human disease. Johansson C, Tumber A, Che K, Cain P, Nowak R, Gileadi C, Oppermann U. Epigenomics 6 89-120 (2014)
  18. Inhibitors of Protein Methyltransferases and Demethylases. Kaniskan HÜ, Martini ML, Jin J. Chem Rev 118 989-1068 (2018)
  19. Dynamic protein methylation in chromatin biology. Ng SS, Yue WW, Oppermann U, Klose RJ. Cell Mol Life Sci 66 407-422 (2009)
  20. Histone demethylases in chromatin biology and beyond. Dimitrova E, Turberfield AH, Klose RJ. EMBO Rep 16 1620-1639 (2015)
  21. IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives. Mondesir J, Willekens C, Touat M, de Botton S. J Blood Med 7 171-180 (2016)
  22. Physiological roles of class I HDAC complex and histone demethylase. Hayakawa T, Nakayama J. J Biomed Biotechnol 2011 129383 (2011)
  23. Targeting histone lysine demethylases - progress, challenges, and the future. Thinnes CC, England KS, Kawamura A, Chowdhury R, Schofield CJ, Hopkinson RJ. Biochim Biophys Acta 1839 1416-1432 (2014)
  24. A peek into the complex realm of histone phosphorylation. Banerjee T, Chakravarti D. Mol Cell Biol 31 4858-4873 (2011)
  25. LSD1 and the chemistry of histone demethylation. Culhane JC, Cole PA. Curr Opin Chem Biol 11 561-568 (2007)
  26. Epigenetic regulation by histone demethylases in hypoxia. Hancock RL, Dunne K, Walport LJ, Flashman E, Kawamura A. Epigenomics 7 791-811 (2015)
  27. Targeting Metalloenzymes for Therapeutic Intervention. Chen AY, Adamek RN, Dick BL, Credille CV, Morrison CN, Cohen SM. Chem Rev 119 1323-1455 (2019)
  28. Chemical and Biochemical Perspectives of Protein Lysine Methylation. Luo M. Chem Rev 118 6656-6705 (2018)
  29. The role of histone demethylases in cancer therapy. Hoffmann I, Roatsch M, Schmitt ML, Carlino L, Pippel M, Sippl W, Jung M. Mol Oncol 6 683-703 (2012)
  30. Epigenetic regulation in cancer progression. Baxter E, Windloch K, Gannon F, Lee JS. Cell Biosci 4 45 (2014)
  31. Structure-function relationships of human JmjC oxygenases-demethylases versus hydroxylases. Markolovic S, Leissing TM, Chowdhury R, Wilkins SE, Lu X, Schofield CJ. Curr Opin Struct Biol 41 62-72 (2016)
  32. Inhibitors of histone demethylases. Lohse B, Kristensen JL, Kristensen LH, Agger K, Helin K, Gajhede M, Clausen RP. Bioorg Med Chem 19 3625-3636 (2011)
  33. Sensing core histone phosphorylation - a matter of perfect timing. Sawicka A, Seiser C. Biochim Biophys Acta 1839 711-718 (2014)
  34. Structure and function of histone H3 lysine 9 methyltransferases and demethylases. Krishnan S, Horowitz S, Trievel RC. Chembiochem 12 254-263 (2011)
  35. The role of the histone demethylase KDM4A in cancer. Guerra-Calderas L, González-Barrios R, Herrera LA, Cantú de León D, Soto-Reyes E. Cancer Genet 208 215-224 (2015)
  36. Epigenetic polypharmacology: from combination therapy to multitargeted drugs. de Lera AR, Ganesan A. Clin Epigenetics 8 105 (2016)
  37. Effect of posttranslational modifications on enzyme function and assembly. Ryšlavá H, Doubnerová V, Kavan D, Vaněk O. J Proteomics 92 80-109 (2013)
  38. A new role for LOX and LOXL2 proteins in transcription regulation. Iturbide A, García de Herreros A, Peiró S. FEBS J 282 1768-1773 (2015)
  39. Prolyl isomerases in gene transcription. Hanes SD. Biochim Biophys Acta 1850 2017-2034 (2015)
  40. 2-Oxoglutarate-dependent dioxygenases are sensors of energy metabolism, oxygen availability, and iron homeostasis: potential role in the regulation of aging process. Salminen A, Kauppinen A, Kaarniranta K. Cell Mol Life Sci 72 3897-3914 (2015)
  41. Recent examples of α-ketoglutarate-dependent mononuclear non-haem iron enzymes in natural product biosyntheses. Gao SS, Naowarojna N, Cheng R, Liu X, Liu P. Nat Prod Rep 35 792-837 (2018)
  42. Molecular basis for substrate recognition by lysine methyltransferases and demethylases. Del Rizzo PA, Trievel RC. Biochim Biophys Acta 1839 1404-1415 (2014)
  43. Base excision repair facilitates a functional relationship between Guanine oxidation and histone demethylation. Li J, Braganza A, Sobol RW. Antioxid Redox Signal 18 2429-2443 (2013)
  44. The Emerging Role of H3K9me3 as a Potential Therapeutic Target in Acute Myeloid Leukemia. Monaghan L, Massett ME, Bunschoten RP, Hoose A, Pirvan PA, Liskamp RMJ, Jørgensen HG, Huang X. Front Oncol 9 705 (2019)
  45. Recent advances in 17beta-hydroxysteroid dehydrogenases. Prehn C, Möller G, Adamski J. J Steroid Biochem Mol Biol 114 72-77 (2009)
  46. Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy. Komar D, Juszczynski P. Clin Epigenetics 12 147 (2020)
  47. Structural genomics and drug discovery: all in the family. Weigelt J, McBroom-Cerajewski LD, Schapira M, Zhao Y, Arrowsmith CH. Curr Opin Chem Biol 12 32-39 (2008)
  48. Advances in Histone Demethylase KDM3A as a Cancer Therapeutic Target. Yoo J, Jeon YH, Cho HY, Lee SW, Kim GW, Lee DH, Kwon SH. Cancers (Basel) 12 E1098 (2020)
  49. Imposing function down a (cupin)-barrel: secondary structure and metal stereochemistry in the αKG-dependent oxygenases. Hangasky JA, Taabazuing CY, Valliere MA, Knapp MJ. Metallomics 5 287-301 (2013)
  50. Small-molecular modulators of cancer-associated epigenetic mechanisms. Itoh Y, Suzuki T, Miyata N. Mol Biosyst 9 873-896 (2013)
  51. Structural definitions of Jumonji family demethylase selectivity. Pilka ES, James T, Lisztwan JH. Drug Discov Today 20 743-749 (2015)
  52. Small molecule epigenetic inhibitors targeted to histone lysine methyltransferases and demethylases. Wang Z, Patel DJ. Q Rev Biophys 46 349-373 (2013)
  53. Defining the orphan functions of lysine acetyltransferases. Montgomery DC, Sorum AW, Meier JL. ACS Chem Biol 10 85-94 (2015)
  54. Epigenetic markers and their cross-talk. Winter S, Fischle W. Essays Biochem 48 45-61 (2010)
  55. A tale of chromatin and transcription in 100 structures. Cramer P. Cell 159 985-994 (2014)
  56. Dynamics of H3K27me3 methylation and demethylation in plant development. Gan ES, Xu Y, Ito T. Plant Signal Behav 10 e1027851 (2015)
  57. Advances and challenges in understanding histone demethylase biology. Nowak RP, Tumber A, Johansson C, Che KH, Brennan P, Owen D, Oppermann U. Curr Opin Chem Biol 33 151-159 (2016)
  58. Modular paths to 'decoding' and 'wiping' histone lysine methylation. Kustatscher G, Ladurner AG. Curr Opin Chem Biol 11 628-635 (2007)
  59. Trimethyllysine: From Carnitine Biosynthesis to Epigenetics. Maas MN, Hintzen JCJ, Porzberg MRB, Mecinović J. Int J Mol Sci 21 E9451 (2020)
  60. Ubiquitin Regulation: The Histone Modifying Enzyme's Story. Wang J, Qiu Z, Wu Y. Cells 7 E118 (2018)
  61. Application of Quantum Computing to Biochemical Systems: A Look to the Future. Cheng HP, Deumens E, Freericks JK, Li C, Sanders BA. Front Chem 8 587143 (2020)
  62. Computational methods for de novo protein design and its applications to the human immunodeficiency virus 1, purine nucleoside phosphorylase, ubiquitin specific protease 7, and histone demethylases. Bellows ML, Floudas CA. Curr Drug Targets 11 264-278 (2010)
  63. High-throughput structural biology of metabolic enzymes and its impact on human diseases. Yue WW, Oppermann U. J Inherit Metab Dis 34 575-581 (2011)
  64. A decade of the human genome sequence--how does the medicinal chemist benefit? Brunschweiger A, Hall J. ChemMedChem 7 194-203 (2012)
  65. Recent Advances with KDM4 Inhibitors and Potential Applications. Wu Q, Young B, Wang Y, Davidoff AM, Rankovic Z, Yang J. J Med Chem 65 9564-9579 (2022)
  66. Adventures in Defining Roles of Oxygenases in the Regulation of Protein Biosynthesis. Walport LJ, Schofield CJ. Chem Rec 18 1760-1781 (2018)
  67. CTCF and Its Multi-Partner Network for Chromatin Regulation. Del Moral-Morales A, Salgado-Albarrán M, Sánchez-Pérez Y, Wenke NK, Baumbach J, Soto-Reyes E. Cells 12 1357 (2023)
  68. Novel Dioxygenases, HIF-α Specific Prolyl-hydroxylase and Asparanginyl-hydroxylase: O2 Switch for Cell Survival. Park H. Toxicol Res 24 101-107 (2008)
  69. The emerging roles of lysine-specific demethylase 4A in cancer: Implications in tumorigenesis and therapeutic opportunities. Yang G, Li C, Tao F, Liu Y, Zhu M, Du Y, Fei C, She Q, Chen J. Genes Dis 11 645-663 (2024)

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