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| - | [[Image:2q8c.jpg|left|200px]]<br /><applet load="2q8c" size="350" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="2q8c, resolution 2.047Å" /> | |
| - | '''Crystal structure of JMJD2A in ternary complex with an histone H3K9me3 peptide and 2-oxoglutarate'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Crystal structure of JMJD2A in ternary complex with an histone H3K9me3 peptide and 2-oxoglutarate== |
| - | JMJD2A is a JmjC histone demethylase (HDM) that catalyzes the, demethylation of di- and trimethylated Lys9 and Lys36 in histone H3, (H3K9me2/3 and H3K36me2/3). Here we present the crystal structures of the, JMJD2A catalytic domain in complex with H3K9me3, H3K36me2 and H3K36me3, peptides. The structures reveal that histone substrates are recognized, through a network of backbone hydrogen bonds and hydrophobic interactions, that deposit the trimethyllysine into the active site. The trimethylated, epsilon-ammonium cation is coordinated within a methylammonium-binding, pocket through carbon-oxygen (CH...O) hydrogen bonds that position one of, the zeta-methyl groups adjacent to the Fe(II) center for hydroxylation and, demethylation. Mutations of the residues comprising this pocket abrogate, demethylation by JMJD2A, with the exception of an S288A substitution, which augments activity, particularly toward H3K9me2. We propose that this, residue modulates the methylation-state specificities of JMJD2 enzymes and, other trimethyllysine-specific JmjC HDMs. | + | <StructureSection load='2q8c' size='340' side='right'caption='[[2q8c]], [[Resolution|resolution]] 2.05Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[2q8c]] is a 4 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=2Q8C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2Q8C 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]] 2.047Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AKG:2-OXOGLUTARIC+ACID'>AKG</scene>, <scene name='pdbligand=M3L:N-TRIMETHYLLYSINE'>M3L</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</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=2q8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q8c OCA], [https://pdbe.org/2q8c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2q8c RCSB], [https://www.ebi.ac.uk/pdbsum/2q8c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2q8c 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> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/q8/2q8c_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2q8c ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | JMJD2A is a JmjC histone demethylase (HDM) that catalyzes the demethylation of di- and trimethylated Lys9 and Lys36 in histone H3 (H3K9me2/3 and H3K36me2/3). Here we present the crystal structures of the JMJD2A catalytic domain in complex with H3K9me3, H3K36me2 and H3K36me3 peptides. The structures reveal that histone substrates are recognized through a network of backbone hydrogen bonds and hydrophobic interactions that deposit the trimethyllysine into the active site. The trimethylated epsilon-ammonium cation is coordinated within a methylammonium-binding pocket through carbon-oxygen (CH...O) hydrogen bonds that position one of the zeta-methyl groups adjacent to the Fe(II) center for hydroxylation and demethylation. Mutations of the residues comprising this pocket abrogate demethylation by JMJD2A, with the exception of an S288A substitution, which augments activity, particularly toward H3K9me2. We propose that this residue modulates the methylation-state specificities of JMJD2 enzymes and other trimethyllysine-specific JmjC HDMs. |
| | | | |
| - | ==About this Structure==
| + | Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase.,Couture JF, Collazo E, Ortiz-Tello PA, Brunzelle JS, Trievel RC Nat Struct Mol Biol. 2007 Aug;14(8):689-95. Epub 2007 Jun 24. PMID:17589523<ref>PMID:17589523</ref> |
| - | 2Q8C is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NI:'>NI</scene>, <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=AKG:'>AKG</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Q8C OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase., Couture JF, Collazo E, Ortiz-Tello PA, Brunzelle JS, Trievel RC, Nat Struct Mol Biol. 2007 Aug;14(8):689-95. Epub 2007 Jun 24. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17589523 17589523]
| + | </div> |
| - | [[Category: Homo sapiens]]
| + | <div class="pdbe-citations 2q8c" style="background-color:#fffaf0;"></div> |
| - | [[Category: Single protein]]
| + | |
| - | [[Category: Brunzelle, J.S.]]
| + | |
| - | [[Category: Collazo, E.]]
| + | |
| - | [[Category: Couture, J-F.]]
| + | |
| - | [[Category: Ortiz-Tello, P.]]
| + | |
| - | [[Category: Trievel, R.C.]]
| + | |
| - | [[Category: AKG]]
| + | |
| - | [[Category: NI]]
| + | |
| - | [[Category: ZN]]
| + | |
| - | [[Category: histone demethylase]]
| + | |
| - | [[Category: hydroxylase]]
| + | |
| - | [[Category: jumonji]]
| + | |
| | | | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Jan 31 10:58:13 2008''
| + | ==See Also== |
| | + | *[[Jumonji domain-containing protein 3D structures|Jumonji domain-containing protein 3D structures]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | + | [[Category: Large Structures]] |
| | + | [[Category: Brunzelle JS]] |
| | + | [[Category: Collazo E]] |
| | + | [[Category: Couture J-F]] |
| | + | [[Category: Ortiz-Tello P]] |
| | + | [[Category: Trievel RC]] |
| Structural highlights
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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
JMJD2A is a JmjC histone demethylase (HDM) that catalyzes the demethylation of di- and trimethylated Lys9 and Lys36 in histone H3 (H3K9me2/3 and H3K36me2/3). Here we present the crystal structures of the JMJD2A catalytic domain in complex with H3K9me3, H3K36me2 and H3K36me3 peptides. The structures reveal that histone substrates are recognized through a network of backbone hydrogen bonds and hydrophobic interactions that deposit the trimethyllysine into the active site. The trimethylated epsilon-ammonium cation is coordinated within a methylammonium-binding pocket through carbon-oxygen (CH...O) hydrogen bonds that position one of the zeta-methyl groups adjacent to the Fe(II) center for hydroxylation and demethylation. Mutations of the residues comprising this pocket abrogate demethylation by JMJD2A, with the exception of an S288A substitution, which augments activity, particularly toward H3K9me2. We propose that this residue modulates the methylation-state specificities of JMJD2 enzymes and other trimethyllysine-specific JmjC HDMs.
Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase.,Couture JF, Collazo E, Ortiz-Tello PA, Brunzelle JS, Trievel RC Nat Struct Mol Biol. 2007 Aug;14(8):689-95. Epub 2007 Jun 24. PMID:17589523[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Couture JF, Collazo E, Ortiz-Tello PA, Brunzelle JS, Trievel RC. Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase. Nat Struct Mol Biol. 2007 Aug;14(8):689-95. Epub 2007 Jun 24. PMID:17589523 doi:http://dx.doi.org/10.1038/nsmb1273
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