5ly1: Difference between revisions

Revision as of 10:54, 12 August 2020

JMJD2A/ KDM4A COMPLEXED WITH NI(II) AND Macrocyclic PEPTIDE Inhibitor CP2 (13-mer)

Structural highlights

5ly1 is a 5 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	CL, GOL, NI, PPI, ZN
NonStd Res:	48V, DTY
Related:	2ox0, 4v2v, 4bis, 4ai9, 2ybp, 5ly2
Gene:	KDM4A, JHDM3A, JMJD2, JMJD2A, KIAA0677 (HUMAN)
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

The JmjC histone demethylases (KDMs) are linked to tumour cell proliferation and are current cancer targets; however, very few highly selective inhibitors for these are available. Here we report cyclic peptide inhibitors of the KDM4A-C with selectivity over other KDMs/2OG oxygenases, including closely related KDM4D/E isoforms. Crystal structures and biochemical analyses of one of the inhibitors (CP2) with KDM4A reveals that CP2 binds differently to, but competes with, histone substrates in the active site. Substitution of the active site binding arginine of CP2 to N-varepsilon-trimethyl-lysine or methylated arginine results in cyclic peptide substrates, indicating that KDM4s may act on non-histone substrates. Targeted modifications to CP2 based on crystallographic and mass spectrometry analyses results in variants with greater proteolytic robustness. Peptide dosing in cells manifests KDM4A target stabilization. Although further development is required to optimize cellular activity, the results reveal the feasibility of highly selective non-metal chelating, substrate-competitive inhibitors of the JmjC KDMs.

Highly selective inhibition of histone demethylases by de novo macrocyclic peptides.,Kawamura A, Munzel M, Kojima T, Yapp C, Bhushan B, Goto Y, Tumber A, Katoh T, King ON, Passioura T, Walport LJ, Hatch SB, Madden S, Muller S, Brennan PE, Chowdhury R, Hopkinson RJ, Suga H, Schofield CJ Nat Commun. 2017 Apr 6;8:14773. doi: 10.1038/ncomms14773. PMID:28382930^[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:https://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:https://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:https://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:https://dx.doi.org/10.1371/journal.pgen.1001390
↑ Kawamura A, Munzel M, Kojima T, Yapp C, Bhushan B, Goto Y, Tumber A, Katoh T, King ON, Passioura T, Walport LJ, Hatch SB, Madden S, Muller S, Brennan PE, Chowdhury R, Hopkinson RJ, Suga H, Schofield CJ. Highly selective inhibition of histone demethylases by de novo macrocyclic peptides. Nat Commun. 2017 Apr 6;8:14773. doi: 10.1038/ncomms14773. PMID:28382930 doi:https://dx.doi.org/10.1038/ncomms14773

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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:https://dx.doi.org/25/15/6404

[2] 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

[3] 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:https://dx.doi.org/10.1371/journal.pgen.1001390

[4] 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:https://dx.doi.org/25/15/6404

[5] 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

[6] 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:https://dx.doi.org/10.1371/journal.pgen.1001390

[7] Kawamura A, Munzel M, Kojima T, Yapp C, Bhushan B, Goto Y, Tumber A, Katoh T, King ON, Passioura T, Walport LJ, Hatch SB, Madden S, Muller S, Brennan PE, Chowdhury R, Hopkinson RJ, Suga H, Schofield CJ. Highly selective inhibition of histone demethylases by de novo macrocyclic peptides. Nat Commun. 2017 Apr 6;8:14773. doi: 10.1038/ncomms14773. PMID:28382930 doi:https://dx.doi.org/10.1038/ncomms14773

[1]

[2]

[3]

[4]

[5]

[6]

[7]

@@ Line 1: / Line 1: @@
 ==JMJD2A/ KDM4A COMPLEXED WITH NI(II) AND Macrocyclic PEPTIDE Inhibitor CP2 (13-mer)==
-<StructureSection load='5ly1' size='340' side='right' caption='[[5ly1]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
+<StructureSection load='5ly1' size='340' side='right'caption='[[5ly1]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5ly1]] is a 5 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LY1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LY1 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5ly1]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LY1 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5LY1 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=PPI:PROPANOIC+ACID'>PPI</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=PPI:PROPANOIC+ACID'>PPI</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=48V:{[(2R)-2,3-DIAMINO-3-OXOPROPYL]SULFANYL}ACETIC+ACID'>48V</scene>, <scene name='pdbligand=DTY:D-TYROSINE'>DTY</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2ox0|2ox0]], [[4v2v|4v2v]], [[4bis|4bis]], [[4ai9|4ai9]], [[2ybp|2ybp]], [[5ly2|5ly2]]</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=5ly1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ly1 OCA], [http://pdbe.org/5ly1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ly1 RCSB], [http://www.ebi.ac.uk/pdbsum/5ly1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ly1 ProSAT]</span></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KDM4A, JHDM3A, JMJD2, JMJD2A, KIAA0677 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5ly1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ly1 OCA], [http://pdbe.org/5ly1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ly1 RCSB], [http://www.ebi.ac.uk/pdbsum/5ly1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ly1 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 5ly1" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Jumonji domain-containing protein 3D structures|Jumonji domain-containing protein 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Chowdhury, R]]
 [[Category: Kawamura, A]]

5ly1: Difference between revisions

Revision as of 10:54, 12 August 2020

JMJD2A/ KDM4A COMPLEXED WITH NI(II) AND Macrocyclic PEPTIDE Inhibitor CP2 (13-mer)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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