6h8p

From Proteopedia

(Difference between revisions)

Revision as of 16:25, 15 August 2018

JMJD2A/ KDM4A COMPLEXED WITH NI(II), NOG AND Histone H1.4(18-32)K26me3 peptide (15-mer)

Structural highlights

6h8p is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
NonStd Res:
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] [H14_HUMAN] Histone H1 protein binds to linker DNA between nucleosomes forming the macromolecular structure known as the chromatin fiber. Histones H1 are necessary for the condensation of nucleosome chains into higher-order structured fibers. Acts also as a regulator of individual gene transcription through chromatin remodeling, nucleosome spacing and DNA methylation (By similarity).

Publication Abstract from PubMed

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.

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. 2007 Jul 5;448(7149):87-91. Epub 2007 Jun 24. PMID:17589501^[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
↑ 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. Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity. Nature. 2007 Jul 5;448(7149):87-91. Epub 2007 Jun 24. PMID:17589501 doi:http://dx.doi.org/10.1038/nature05971

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6h8p"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6h8p is ON HOLD
+==JMJD2A/ KDM4A COMPLEXED WITH NI(II), NOG AND Histone H1.4(18-32)K26me3 peptide (15-mer)==
+<StructureSection load='6h8p' size='340' side='right' caption='[[6h8p]], [[Resolution|resolution]] 1.98&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6h8p]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6H8P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6H8P FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=OGA:N-OXALYLGLYCINE'>OGA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=M3L:N-TRIMETHYLLYSINE'>M3L</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6h8p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6h8p OCA], [http://pdbe.org/6h8p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6h8p RCSB], [http://www.ebi.ac.uk/pdbsum/6h8p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6h8p ProSAT]</span></td></tr>
+</table>
+== Function ==
+[[http://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>  [[http://www.uniprot.org/uniprot/H14_HUMAN H14_HUMAN]] Histone H1 protein binds to linker DNA between nucleosomes forming the macromolecular structure known as the chromatin fiber. Histones H1 are necessary for the condensation of nucleosome chains into higher-order structured fibers. Acts also as a regulator of individual gene transcription through chromatin remodeling, nucleosome spacing and DNA methylation (By similarity).
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+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.
-Authors: Chowdhury, R., Walport, L.J., Schofield, C.J.
+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. 2007 Jul 5;448(7149):87-91. Epub 2007 Jun 24. PMID:17589501<ref>PMID:17589501</ref>
-Description: JMJD2A/ KDM4A COMPLEXED WITH NI(II), NOG AND Histone H1.4(18-32)K26me3 peptide (15-mer)
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6h8p" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Chowdhury, R]]
-[[Category: Schofield, C.J]]
+[[Category: Schofield, C J]]
-[[Category: Walport, L.J]]
+[[Category: Walport, L J]]
+[[Category: 2-oxoglutarate]]
+[[Category: Chromatin regulator]]
+[[Category: Demethylase]]
+[[Category: Dioxygenase]]
+[[Category: Double-stranded beta helix]]
+[[Category: Dsbh]]
+[[Category: Epigenetic and transcription regulation]]
+[[Category: Facial triad]]
+[[Category: Histone]]
+[[Category: Hydroxylation]]
+[[Category: Iron]]
+[[Category: Jmjc domain]]
+[[Category: Jmjd2a]]
+[[Category: Kdm4a]]
+[[Category: Metal binding protein]]
+[[Category: Non-heme]]
+[[Category: Oxidoreductase]]
+[[Category: Oxygenase]]

6h8p

From Proteopedia

Revision as of 16:25, 15 August 2018

JMJD2A/ KDM4A COMPLEXED WITH NI(II), NOG AND Histone H1.4(18-32)K26me3 peptide (15-mer)

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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