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5eap

From Proteopedia

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Crystal structure of human WDR5 in complex with compound 9e

Structural highlights

5eap is a 1 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 1.73Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

WDR5_HUMAN Contributes to histone modification. May position the N-terminus of histone H3 for efficient trimethylation at 'Lys-4'. As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. May regulate osteoblasts differentiation.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

WD repeat-containing protein 5 (WDR5) is an important component of the multiprotein complex essential for activating mixed-lineage leukemia 1 (MLL1). Rearrangement of the MLL1 gene is associated with onset and progression of acute myeloid and lymphoblastic leukemias, and targeting the WDR5-MLL1 interaction may result in new cancer therapeutics. Our previous work showed that binding of small molecule ligands to WDR5 can modulate its interaction with MLL1, suppressing MLL1 methyltransferase activity. Initial structure-activity relationship studies identified N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides as potent and selective antagonists of this protein-protein interaction. Guided by crystal structure data and supported by in silico library design, we optimized the scaffold by varying the C-1 benzamide and C-5 substituents. This allowed us to develop the first highly potent (Kdisp < 100 nM) small molecule antagonists of the WDR5-MLL1 interaction and demonstrate that N-(4-(4-methylpiperazin-1-yl)-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)-6-oxo-4 -(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide 16d (OICR-9429) is a potent and selective chemical probe suitable to help dissect the biological role of WDR5.

Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1).,Getlik M, Smil D, Zepeda-Velazquez C, Bolshan Y, Poda G, Wu H, Dong A, Kuznetsova E, Marcellus R, Senisterra G, Dombrovski L, Hajian T, Kiyota T, Schapira M, Arrowsmith CH, Brown PJ, Vedadi M, Al-Awar R J Med Chem. 2016 Mar 24;59(6):2478-96. doi: 10.1021/acs.jmedchem.5b01630. Epub, 2016 Mar 9. PMID:26958703^[6]

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

References

↑ Patel A, Dharmarajan V, Vought VE, Cosgrove MS. On the mechanism of multiple lysine methylation by the human mixed lineage leukemia protein-1 (MLL1) core complex. J Biol Chem. 2009 Sep 4;284(36):24242-56. Epub 2009 Jun 25. PMID:19556245 doi:M109.014498
↑ Guelman S, Kozuka K, Mao Y, Pham V, Solloway MJ, Wang J, Wu J, Lill JR, Zha J. The double-histone-acetyltransferase complex ATAC is essential for mammalian development. Mol Cell Biol. 2009 Mar;29(5):1176-88. doi: 10.1128/MCB.01599-08. Epub 2008 Dec, 22. PMID:19103755 doi:10.1128/MCB.01599-08
↑ Cai Y, Jin J, Swanson SK, Cole MD, Choi SH, Florens L, Washburn MP, Conaway JW, Conaway RC. Subunit composition and substrate specificity of a MOF-containing histone acetyltransferase distinct from the male-specific lethal (MSL) complex. J Biol Chem. 2010 Feb 12;285(7):4268-72. doi: 10.1074/jbc.C109.087981. Epub 2009 , Dec 14. PMID:20018852 doi:10.1074/jbc.C109.087981
↑ Han Z, Guo L, Wang H, Shen Y, Deng XW, Chai J. Structural basis for the specific recognition of methylated histone H3 lysine 4 by the WD-40 protein WDR5. Mol Cell. 2006 Apr 7;22(1):137-44. PMID:16600877 doi:10.1016/j.molcel.2006.03.018
↑ Couture JF, Collazo E, Trievel RC. Molecular recognition of histone H3 by the WD40 protein WDR5. Nat Struct Mol Biol. 2006 Aug;13(8):698-703. Epub 2006 Jul 9. PMID:16829960 doi:10.1038/nsmb1116
↑ Getlik M, Smil D, Zepeda-Velazquez C, Bolshan Y, Poda G, Wu H, Dong A, Kuznetsova E, Marcellus R, Senisterra G, Dombrovski L, Hajian T, Kiyota T, Schapira M, Arrowsmith CH, Brown PJ, Vedadi M, Al-Awar R. Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1). J Med Chem. 2016 Mar 24;59(6):2478-96. doi: 10.1021/acs.jmedchem.5b01630. Epub, 2016 Mar 9. PMID:26958703 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01630

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/5eap"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human WDR5 in complex with compound 9e==
-<StructureSection load='5eap' size='340' side='right' caption='[[5eap]], [[Resolution|resolution]] 1.73&Aring;' scene=''>
+<StructureSection load='5eap' size='340' side='right'caption='[[5eap]], [[Resolution|resolution]] 1.73&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5eap]] is a 1 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=5EAP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EAP FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5eap]] is a 1 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=5EAP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EAP FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5MO:N-[5-(2,3-DIHYDRO-1-BENZOFURAN-5-YL)-2-(4-METHYLPIPERAZIN-1-YL)PHENYL]-3-METHYLBENZAMIDE'>5MO</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.73&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5eal|5eal]], [[5eam|5eam]], [[5ear|5ear]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5MO:N-[5-(2,3-DIHYDRO-1-BENZOFURAN-5-YL)-2-(4-METHYLPIPERAZIN-1-YL)PHENYL]-3-METHYLBENZAMIDE'>5MO</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">WDR5, BIG3 ([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'>[https://proteopedia.org/fgij/fg.htm?mol=5eap FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eap OCA], [https://pdbe.org/5eap PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5eap RCSB], [https://www.ebi.ac.uk/pdbsum/5eap PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5eap ProSAT]</span></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=5eap FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eap OCA], [http://pdbe.org/5eap PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5eap RCSB], [http://www.ebi.ac.uk/pdbsum/5eap PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5eap ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/WDR5_HUMAN WDR5_HUMAN]] Contributes to histone modification. May position the N-terminus of histone H3 for efficient trimethylation at 'Lys-4'. As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. May regulate osteoblasts differentiation.<ref>PMID:19556245</ref> <ref>PMID:19103755</ref> <ref>PMID:20018852</ref> <ref>PMID:16600877</ref> <ref>PMID:16829960</ref>
+[https://www.uniprot.org/uniprot/WDR5_HUMAN WDR5_HUMAN] Contributes to histone modification. May position the N-terminus of histone H3 for efficient trimethylation at 'Lys-4'. As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. May regulate osteoblasts differentiation.<ref>PMID:19556245</ref> <ref>PMID:19103755</ref> <ref>PMID:20018852</ref> <ref>PMID:16600877</ref> <ref>PMID:16829960</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 21: @@
 ==See Also==
-*[[WD repeat-containing protein|WD repeat-containing protein]]
+*[[WD-repeat protein 3D structures|WD-repeat protein 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: AL-AWAR, R]]
+[[Category: Large Structures]]
-[[Category: Arrowsmith, C H]]
+[[Category: AL-AWAR R]]
-[[Category: BOLSHAN, Y]]
+[[Category: Arrowsmith CH]]
-[[Category: BROWN, P J]]
+[[Category: BOLSHAN Y]]
-[[Category: Bountra, C]]
+[[Category: BROWN PJ]]
-[[Category: DOMBROVSKI, L]]
+[[Category: Bountra C]]
-[[Category: DONG, A]]
+[[Category: DOMBROVSKI L]]
-[[Category: Edwards, A M]]
+[[Category: DONG A]]
-[[Category: GETLIK, M]]
+[[Category: Edwards AM]]
-[[Category: PODA, G]]
+[[Category: GETLIK M]]
-[[Category: SCHAPIRA, M]]
+[[Category: PODA G]]
-[[Category: SENISTERRA, G]]
+[[Category: SCHAPIRA M]]
-[[Category: Structural genomic]]
+[[Category: SENISTERRA G]]
-[[Category: SMIL, D]]
+[[Category: SMIL D]]
-[[Category: VEDADI, M]]
+[[Category: VEDADI M]]
-[[Category: WALKER, J R]]
+[[Category: WALKER JR]]
-[[Category: WU, H]]
+[[Category: WU H]]
-[[Category: Compound 9e]]
-[[Category: Sgc]]
-[[Category: Transcription-transcription inhibitor complex]]
-[[Category: Wdr5]]

5eap

From Proteopedia

Current revision

Crystal structure of human WDR5 in complex with compound 9e

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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