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Observed bromodomain flexibility reveals histone peptide- and small molecule ligand-compatible forms of ATAD2.

Poncet-Montange G, Zhan Y, Bardenhagen JP, Petrocchi A, Leo E, Shi X, Lee GR, Leonard PG, Geck Do MK, Cardozo MG, Andersen JN, Palmer WS, Jones P, Ladbury JE
Biochem J 466 337-46 (2015)
Related entries: 4tt2, 4tt4, 4tt6, 4tte, 4tu6

Cited: 25 times
EuropePMC logo PMID: 25486442

Abstract

Preventing histone recognition by bromodomains emerges as an attractive therapeutic approach in cancer. Overexpression of ATAD2 (ATPase family AAA domain-containing 2 isoform A) in cancer cells is associated with poor prognosis making the bromodomain of ATAD2 a promising epigenetic therapeutic target. In the development of an in vitro assay and identification of small molecule ligands, we conducted structure-guided studies which revealed a conformationally flexible ATAD2 bromodomain. Structural studies on apo-, peptide-and small molecule-ATAD2 complexes (by co-crystallization) revealed that the bromodomain adopts a 'closed', histone-compatible conformation and a more 'open' ligand-compatible conformation of the binding site respectively. An unexpected conformational change of the conserved asparagine residue plays an important role in driving the peptide-binding conformation remodelling. We also identified dimethylisoxazole-containing ligands as ATAD2 binders which aided in the validation of the in vitro screen and in the analysis of these conformational studies.

Reviews - 4tu4 mentioned but not cited (1)

  1. AAA ATPases as therapeutic targets: Structure, functions, and small-molecule inhibitors. Zhang G, Li S, Cheng KW, Chou TF. Eur J Med Chem 219 113446 (2021)

Articles - 4tu4 mentioned but not cited (1)

  1. Observed bromodomain flexibility reveals histone peptide- and small molecule ligand-compatible forms of ATAD2. Poncet-Montange G, Zhan Y, Bardenhagen JP, Petrocchi A, Leo E, Shi X, Lee GR, Leonard PG, Geck Do MK, Cardozo MG, Andersen JN, Palmer WS, Jones P, Ladbury JE. Biochem J 466 337-346 (2015)


Reviews citing this publication (7)

  1. Lysine Acetylation Goes Global: From Epigenetics to Metabolism and Therapeutics. Ali I, Conrad RJ, Verdin E, Ott M. Chem Rev 118 1216-1252 (2018)
  2. Biological function and histone recognition of family IV bromodomain-containing proteins. Lloyd JT, Glass KC. J Cell Physiol 233 1877-1886 (2018)
  3. ATAD2 in cancer: a pharmacologically challenging but tractable target. Hussain M, Zhou Y, Song Y, Hameed HMA, Jiang H, Tu Y, Zhang J. Expert Opin Ther Targets 22 85-96 (2018)
  4. Functional Roles of Bromodomain Proteins in Cancer. Boyson SP, Gao C, Quinn K, Boyd J, Paculova H, Frietze S, Glass KC. Cancers (Basel) 13 3606 (2021)
  5. Binding Mode of Acetylated Histones to Bromodomains: Variations on a Common Motif. Marchand JR, Caflisch A. ChemMedChem 10 1327-1333 (2015)
  6. Targeting BRD9 for Cancer Treatment: A New Strategy. Zhu X, Liao Y, Tang L. Onco Targets Ther 13 13191-13200 (2020)
  7. ATPase family AAA domain-containing protein 2 (ATAD2): From an epigenetic modulator to cancer therapeutic target. Fu J, Zhang J, Chen X, Liu Z, Yang X, He Z, Hao Y, Liu B, Yao D. Theranostics 13 787-809 (2023)

Articles citing this publication (16)

  1. Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor. Palmer WS, Poncet-Montange G, Liu G, Petrocchi A, Reyna N, Subramanian G, Theroff J, Yau A, Kost-Alimova M, Bardenhagen JP, Leo E, Shepard HE, Tieu TN, Shi X, Zhan Y, Zhao S, Barton MC, Draetta G, Toniatti C, Jones P, Geck Do M, Andersen JN. J Med Chem 59 1440-1454 (2016)
  2. Gene-by-environment interactions in urban populations modulate risk phenotypes. Favé MJ, Lamaze FC, Soave D, Hodgkinson A, Gauvin H, Bruat V, Grenier JC, Gbeha E, Skead K, Smargiassi A, Johnson M, Idaghdour Y, Awadalla P. Nat Commun 9 827 (2018)
  3. TRIM66 reads unmodified H3R2K4 and H3K56ac to respond to DNA damage in embryonic stem cells. Chen J, Wang Z, Guo X, Li F, Wei Q, Chen X, Gong D, Xu Y, Chen W, Liu Y, Kang J, Shi Y. Nat Commun 10 4273 (2019)
  4. Synthesis and Demonstration of the Biological Relevance of sp3 -rich Scaffolds Distantly Related to Natural Product Frameworks. Foley DJ, Craven PGE, Collins PM, Doveston RG, Aimon A, Talon R, Churcher I, von Delft F, Marsden SP, Nelson A. Chemistry 23 15227-15232 (2017)
  5. Development of novel cellular histone-binding and chromatin-displacement assays for bromodomain drug discovery. Zhan Y, Kost-Alimova M, Shi X, Leo E, Bardenhagen JP, Shepard HE, Appikonda S, Vangamudi B, Zhao S, Tieu TN, Jiang S, Heffernan TP, Marszalek JR, Toniatti C, Draetta G, Tyler J, Barton M, Jones P, Palmer WS, Geck Do MK, Andersen JN. Epigenetics Chromatin 8 37 (2015)
  6. The ATAD2 bromodomain binds different acetylation marks on the histone H4 in similar fuzzy complexes. Langini C, Caflisch A, Vitalis A. J Biol Chem 292 16734-16745 (2017)
  7. The ATAD2/ANCCA homolog Yta7 cooperates with Scm3HJURP to deposit Cse4CENP-A at the centromere in yeast. Shahnejat-Bushehri S, Ehrenhofer-Murray AE. Proc Natl Acad Sci U S A 117 5386-5393 (2020)
  8. Disulfide bridge formation influences ligand recognition by the ATAD2 bromodomain. Gay JC, Eckenroth BE, Evans CM, Langini C, Carlson S, Lloyd JT, Caflisch A, Glass KC. Proteins 87 157-167 (2019)
  9. Discovery of a hidden transient state in all bromodomain families. Raich L, Meier K, Günther J, Christ CD, Noé F, Olsson S. Proc Natl Acad Sci U S A 118 e2017427118 (2021)
  10. Mechanistic insights into peptide and ligand binding of the ATAD2-bromodomain via atomistic simulations disclosing a role of induced fit and conformational selection. Zhou Y, Hussain M, Kuang G, Zhang J, Tu Y. Phys Chem Chem Phys 20 23222-23232 (2018)
  11. Coordination of Di-Acetylated Histone Ligands by the ATAD2 Bromodomain. Evans CM, Phillips M, Malone KL, Tonelli M, Cornilescu G, Cornilescu C, Holton SJ, Gorjánácz M, Wang L, Carlson S, Gay JC, Nix JC, Demeler B, Markley JL, Glass KC. Int J Mol Sci 22 9128 (2021)
  12. Structural Insights into the Recognition of Mono- and Diacetylated Histones by the ATAD2B Bromodomain. Lloyd JT, McLaughlin K, Lubula MY, Gay JC, Dest A, Gao C, Phillips M, Tonelli M, Cornilescu G, Marunde MR, Evans CM, Boyson SP, Carlson S, Keogh MC, Markley JL, Frietze S, Glass KC. J Med Chem 63 12799-12813 (2020)
  13. The BRPF1 bromodomain is a molecular reader of di-acetyllysine. Obi JO, Lubula MY, Cornilescu G, Henrickson A, McGuire K, Evans CM, Phillips M, Boyson SP, Demeler B, Markley JL, Glass KC. Curr Res Struct Biol 2 104-115 (2020)
  14. Prognostic value of ATPase family, AAA+ domain containing 2 expression in human cancers: A systematic review and meta-analysis. Han HJ, Huang QY, Huang LJ, Chang F, Diao QZ. Medicine (Baltimore) 98 e17180 (2019)
  15. Protein dynamics and structural waters in bromodomains. Zhang X, Chen K, Wu YD, Wiest O. PLoS One 12 e0186570 (2017)
  16. The role of loop dynamics in the prediction of ligand-protein binding enthalpy. Çınaroğlu SS, Biggin PC. Chem Sci 14 6792-6805 (2023)


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