5a7n

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of human JMJD2A in complex with compound 43

Structural highlights

5a7n is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.39Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KDM4A_HUMAN Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27' nor H4 'Lys-20'. Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues. Demethylation of Lys residue generates formaldehyde and succinate. Participates in transcriptional repression of ASCL2 and E2F-responsive promoters via the recruitment of histone deacetylases and NCOR1, respectively.^[1] ^[2] ^[3] Isoform 2: Crucial for muscle differentiation, promotes transcriptional activation of the Myog gene by directing the removal of repressive chromatin marks at its promoter. Lacks the N-terminal demethylase domain.^[4] ^[5] ^[6]

Publication Abstract from PubMed

Development of tool molecules that inhibit Jumonji demethylases allows for the investigation of cancer-associated transcription. While scaffolds such as 2,4-pyridinedicarboxylic acid (2,4-PDCA) are potent inhibitors, they exhibit limited selectivity. To discover new inhibitors for the KDM4 demethylases, enzymes overexpressed in several cancers, we docked a library of 600000 fragments into the high-resolution structure of KDM4A. Among the most interesting chemotypes were the 5-aminosalicylates, which docked in two distinct but overlapping orientations. Docking poses informed the design of covalently linked fragment compounds, which were further derivatized. This combined approach improved affinity by approximately 3 log-orders to yield compound 35 (Ki = 43 nM). Several hybrid inhibitors were selective for KDM4C over the related enzymes FIH, KDM2A, and KDM6B while lacking selectivity against the KDM3 and KDM5 subfamilies. Cocrystal structures corroborated the docking predictions. This study extends the use of structure-based docking from fragment discovery to fragment linking optimization, yielding novel KDM4 inhibitors.

Docking and Linking of Fragments To Discover Jumonji Histone Demethylase Inhibitors.,Korczynska M, Le DD, Younger N, Gregori-Puigjane E, Tumber A, Krojer T, Velupillai S, Gileadi C, Nowak RP, Iwasa E, Pollock SB, Ortiz Torres I, Oppermann U, Shoichet BK, Fujimori DG J Med Chem. 2015 Dec 23. PMID:26699912^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zhang D, Yoon HG, Wong J. JMJD2A is a novel N-CoR-interacting protein and is involved in repression of the human transcription factor achaete scute-like homologue 2 (ASCL2/Hash2). Mol Cell Biol. 2005 Aug;25(15):6404-14. PMID:16024779 doi:http://dx.doi.org/25/15/6404
↑ Whetstine JR, Nottke A, Lan F, Huarte M, Smolikov S, Chen Z, Spooner E, Li E, Zhang G, Colaiacovo M, Shi Y. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell. 2006 May 5;125(3):467-81. Epub 2006 Apr 6. PMID:16603238 doi:10.1016/j.cell.2006.03.028
↑ Verrier L, Escaffit F, Chailleux C, Trouche D, Vandromme M. A new isoform of the histone demethylase JMJD2A/KDM4A is required for skeletal muscle differentiation. PLoS Genet. 2011 Jun;7(6):e1001390. doi: 10.1371/journal.pgen.1001390. Epub 2011 , Jun 2. PMID:21694756 doi:http://dx.doi.org/10.1371/journal.pgen.1001390
↑ Zhang D, Yoon HG, Wong J. JMJD2A is a novel N-CoR-interacting protein and is involved in repression of the human transcription factor achaete scute-like homologue 2 (ASCL2/Hash2). Mol Cell Biol. 2005 Aug;25(15):6404-14. PMID:16024779 doi:http://dx.doi.org/25/15/6404
↑ Whetstine JR, Nottke A, Lan F, Huarte M, Smolikov S, Chen Z, Spooner E, Li E, Zhang G, Colaiacovo M, Shi Y. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell. 2006 May 5;125(3):467-81. Epub 2006 Apr 6. PMID:16603238 doi:10.1016/j.cell.2006.03.028
↑ Verrier L, Escaffit F, Chailleux C, Trouche D, Vandromme M. A new isoform of the histone demethylase JMJD2A/KDM4A is required for skeletal muscle differentiation. PLoS Genet. 2011 Jun;7(6):e1001390. doi: 10.1371/journal.pgen.1001390. Epub 2011 , Jun 2. PMID:21694756 doi:http://dx.doi.org/10.1371/journal.pgen.1001390
↑ Korczynska M, Le DD, Younger N, Gregori-Puigjane E, Tumber A, Krojer T, Velupillai S, Gileadi C, Nowak RP, Iwasa E, Pollock SB, Ortiz Torres I, Oppermann U, Shoichet BK, Fujimori DG. Docking and Linking of Fragments To Discover Jumonji Histone Demethylase Inhibitors. J Med Chem. 2015 Dec 23. PMID:26699912 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01527

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5a7n"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5a7n is ON HOLD  until Paper Publication
+==Crystal structure of human JMJD2A in complex with compound 43==
+<StructureSection load='5a7n' size='340' side='right'caption='[[5a7n]], [[Resolution|resolution]] 2.39&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5a7n]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5A7N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5A7N FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.39&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=VAO:2-(5-CYANO-2-OXIDANYL-PHENYL)PYRIDINE-4-CARBOXYLIC+ACID'>VAO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5a7n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5a7n OCA], [https://pdbe.org/5a7n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5a7n RCSB], [https://www.ebi.ac.uk/pdbsum/5a7n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5a7n ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/KDM4A_HUMAN KDM4A_HUMAN] Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27' nor H4 'Lys-20'. Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues. Demethylation of Lys residue generates formaldehyde and succinate. Participates in transcriptional repression of ASCL2 and E2F-responsive promoters via the recruitment of histone deacetylases and NCOR1, respectively.<ref>PMID:16024779</ref> <ref>PMID:16603238</ref> <ref>PMID:21694756</ref>   Isoform 2: Crucial for muscle differentiation, promotes transcriptional activation of the Myog gene by directing the removal of repressive chromatin marks at its promoter. Lacks the N-terminal demethylase domain.<ref>PMID:16024779</ref> <ref>PMID:16603238</ref> <ref>PMID:21694756</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Development of tool molecules that inhibit Jumonji demethylases allows for the investigation of cancer-associated transcription. While scaffolds such as 2,4-pyridinedicarboxylic acid (2,4-PDCA) are potent inhibitors, they exhibit limited selectivity. To discover new inhibitors for the KDM4 demethylases, enzymes overexpressed in several cancers, we docked a library of 600000 fragments into the high-resolution structure of KDM4A. Among the most interesting chemotypes were the 5-aminosalicylates, which docked in two distinct but overlapping orientations. Docking poses informed the design of covalently linked fragment compounds, which were further derivatized. This combined approach improved affinity by approximately 3 log-orders to yield compound 35 (Ki = 43 nM). Several hybrid inhibitors were selective for KDM4C over the related enzymes FIH, KDM2A, and KDM6B while lacking selectivity against the KDM3 and KDM5 subfamilies. Cocrystal structures corroborated the docking predictions. This study extends the use of structure-based docking from fragment discovery to fragment linking optimization, yielding novel KDM4 inhibitors.
-Authors: Nowak, R., Velupillai, S., Krojer, T., Gileadi, C., Johansson, C., Korczynska, M., Le, D.D., Younger, N., Gregori-Puigjane, E., Tumber, A., Iwasa, E., Pollock, S.B., Ortiz Torres, I., Williams, E., Riesebos, E., Von Delft, F., Arrowsmith, C.H., Bountra, C., Edwards, A., Shoichet, B.K., Fujimori, D.G., Oppermann, U.
+Docking and Linking of Fragments To Discover Jumonji Histone Demethylase Inhibitors.,Korczynska M, Le DD, Younger N, Gregori-Puigjane E, Tumber A, Krojer T, Velupillai S, Gileadi C, Nowak RP, Iwasa E, Pollock SB, Ortiz Torres I, Oppermann U, Shoichet BK, Fujimori DG J Med Chem. 2015 Dec 23. PMID:26699912<ref>PMID:26699912</ref>
-Description: Crystal structure of human JMJD2A in complex with compound 43
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Nowak, R]]
+<div class="pdbe-citations 5a7n" style="background-color:#fffaf0;"></div>
-[[Category: Ortiz Torres, I]]
-[[Category: Korczynska, M]]
+==See Also==
-[[Category: Velupillai, S]]
+*[[Jumonji domain-containing protein 3D structures|Jumonji domain-containing protein 3D structures]]
-[[Category: Shoichet, B.K]]
+== References ==
-[[Category: Younger, N]]
+<references/>
-[[Category: Iwasa, E]]
+__TOC__
-[[Category: Gregori-Puigjane, E]]
+</StructureSection>
-[[Category: Tumber, A]]
+[[Category: Homo sapiens]]
-[[Category: Krojer, T]]
+[[Category: Large Structures]]
-[[Category: Bountra, C]]
+[[Category: Arrowsmith CH]]
-[[Category: Pollock, S.B]]
+[[Category: Bountra C]]
-[[Category: Fujimori, D.G]]
+[[Category: Edwards A]]
-[[Category: Arrowsmith, C.H]]
+[[Category: Fujimori DG]]
-[[Category: Le, D.D]]
+[[Category: Gileadi C]]
-[[Category: Gileadi, C]]
+[[Category: Gregori-Puigjane E]]
-[[Category: Oppermann, U]]
+[[Category: Iwasa E]]
-[[Category: Williams, E]]
+[[Category: Johansson C]]
-[[Category: Von Delft, F]]
+[[Category: Korczynska M]]
-[[Category: Johansson, C]]
+[[Category: Krojer T]]
-[[Category: Edwards, A]]
+[[Category: Le DD]]
-[[Category: Riesebos, E]]
+[[Category: Nowak R]]
+[[Category: Oppermann U]]
+[[Category: Ortiz Torres I]]
+[[Category: Pollock SB]]
+[[Category: Riesebos E]]
+[[Category: Shoichet BK]]
+[[Category: Tumber A]]
+[[Category: Velupillai S]]
+[[Category: Williams E]]
+[[Category: Younger N]]
+[[Category: Von Delft F]]

5a7n

From Proteopedia

Current revision

Crystal structure of human JMJD2A in complex with compound 43

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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