5vmp

From Proteopedia

(Difference between revisions)

Revision as of 10:12, 27 September 2017

Crystal Structure of Human KDM4 with Small Molecule Inhibitor QC5714

Structural highlights

5vmp is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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

Histone lysine demethylases (KDMs) play a vital role in the regulation of chromatin-related processes. Herein, we describe our discovery of a series of potent KDM4 inhibitors that are both cell permeable and antiproliferative in cancer models. The modulation of histone H3K9me3 and H3K36me3 upon compound treatment was verified by homogeneous time-resolved fluorescence assay and by mass spectroscopy detection. Optimization of the series using structure-based drug design led to compound 6 (QC6352), a potent KDM4 family inhibitor that is efficacious in breast and colon cancer PDX models.

Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models.,Chen YK, Bonaldi T, Cuomo A, Del Rosario JR, Hosfield DJ, Kanouni T, Kao SC, Lai C, Lobo NA, Matuszkiewicz J, McGeehan A, O'Connell SM, Shi L, Stafford JA, Stansfield RK, Veal JM, Weiss MS, Yuen NY, Wallace MB ACS Med Chem Lett. 2017 Jul 27;8(8):869-874. doi: 10.1021/acsmedchemlett.7b00220., eCollection 2017 Aug 10. PMID:28835804^[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
↑ Chen YK, Bonaldi T, Cuomo A, Del Rosario JR, Hosfield DJ, Kanouni T, Kao SC, Lai C, Lobo NA, Matuszkiewicz J, McGeehan A, O'Connell SM, Shi L, Stafford JA, Stansfield RK, Veal JM, Weiss MS, Yuen NY, Wallace MB. Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models. ACS Med Chem Lett. 2017 Jul 27;8(8):869-874. doi: 10.1021/acsmedchemlett.7b00220., eCollection 2017 Aug 10. PMID:28835804 doi:http://dx.doi.org/10.1021/acsmedchemlett.7b00220

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/5vmp"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5vmp is ON HOLD
+==Crystal Structure of Human KDM4 with Small Molecule Inhibitor QC5714==
+<StructureSection load='5vmp' size='340' side='right' caption='[[5vmp]], [[Resolution|resolution]] 2.48&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5vmp]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VMP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VMP FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9FJ:3-({[(1R)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic+acid'>9FJ</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5vmp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vmp OCA], [http://pdbe.org/5vmp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vmp RCSB], [http://www.ebi.ac.uk/pdbsum/5vmp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vmp 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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Histone lysine demethylases (KDMs) play a vital role in the regulation of chromatin-related processes. Herein, we describe our discovery of a series of potent KDM4 inhibitors that are both cell permeable and antiproliferative in cancer models. The modulation of histone H3K9me3 and H3K36me3 upon compound treatment was verified by homogeneous time-resolved fluorescence assay and by mass spectroscopy detection. Optimization of the series using structure-based drug design led to compound 6 (QC6352), a potent KDM4 family inhibitor that is efficacious in breast and colon cancer PDX models.
-Authors: Hosfield, D.J., Wallace, M.
+Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models.,Chen YK, Bonaldi T, Cuomo A, Del Rosario JR, Hosfield DJ, Kanouni T, Kao SC, Lai C, Lobo NA, Matuszkiewicz J, McGeehan A, O'Connell SM, Shi L, Stafford JA, Stansfield RK, Veal JM, Weiss MS, Yuen NY, Wallace MB ACS Med Chem Lett. 2017 Jul 27;8(8):869-874. doi: 10.1021/acsmedchemlett.7b00220., eCollection 2017 Aug 10. PMID:28835804<ref>PMID:28835804</ref>
-Description: Crystal Structure of KDM4 with QC5714
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Hosfield, D.J]]
+<div class="pdbe-citations 5vmp" style="background-color:#fffaf0;"></div>
-[[Category: Wallace, M]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Hosfield, D J]]
+[[Category: Demethylase]]
+[[Category: Epigenetic]]
+[[Category: Inhibitor-complex]]
+[[Category: Kdm4]]
+[[Category: Oxidoreductase-inhibitor complex]]

5vmp

From Proteopedia

Revision as of 10:12, 27 September 2017

Crystal Structure of Human KDM4 with Small Molecule Inhibitor QC5714

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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