4gmb

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==Crystal structure of human WD repeat domain 5 with compound MM-402==
==Crystal structure of human WD repeat domain 5 with compound MM-402==
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<StructureSection load='4gmb' size='340' side='right'caption='[[4gmb]]' scene=''>
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<StructureSection load='4gmb' size='340' side='right'caption='[[4gmb]], [[Resolution|resolution]] 2.78&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GMB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GMB FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4gmb]] is a 2 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=4GMB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GMB FirstGlance]. <br>
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</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=4gmb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gmb OCA], [https://pdbe.org/4gmb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gmb RCSB], [https://www.ebi.ac.uk/pdbsum/4gmb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gmb ProSAT]</span></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.781&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0XQ:(2R)-2,8-DIAMINO-2-METHYLOCTANOIC+ACID'>0XQ</scene>, <scene name='pdbligand=ABA:ALPHA-AMINOBUTYRIC+ACID'>ABA</scene>, <scene name='pdbligand=ALQ:2-METHYL-PROPIONIC+ACID'>ALQ</scene>, <scene name='pdbligand=PG9:D-PHENYLGLYCINE'>PG9</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4gmb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gmb OCA], [https://pdbe.org/4gmb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gmb RCSB], [https://www.ebi.ac.uk/pdbsum/4gmb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gmb ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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We report herein the design, synthesis, and evaluation of macrocyclic peptidomimetics that bind to WD repeat domain 5 (WDR5) and block the WDR5-mixed lineage leukemia (MLL) protein-protein interaction. Compound 18 (MM-589) binds to WDR5 with an IC50 value of 0.90 nM (Ki value &lt;1 nM) and inhibits the MLL H3K4 methyltransferase (HMT) activity with an IC50 value of 12.7 nM. Compound 18 potently and selectively inhibits cell growth in human leukemia cell lines harboring MLL translocations and is &gt;40 times better than the previously reported compound MM-401. Cocrystal structures of 16 and 18 complexed with WDR5 provide structural basis for their high affinity binding to WDR5. Additionally, we have developed and optimized a new AlphaLISA-based MLL HMT functional assay to facilitate the functional evaluation of these designed compounds. Compound 18 represents the most potent inhibitor of the WDR5-MLL interaction reported to date, and further optimization of 18 may yield a new therapy for acute leukemia.
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Discovery of a Highly Potent, Cell-Permeable Macrocyclic Peptidomimetic (MM-589) Targeting the WD Repeat Domain 5 Protein (WDR5)-Mixed Lineage Leukemia (MLL) Protein-Protein Interaction.,Karatas H, Li Y, Liu L, Ji J, Lee S, Chen Y, Yang J, Huang L, Bernard D, Xu J, Townsend EC, Cao F, Ran X, Li X, Wen B, Sun D, Stuckey JA, Lei M, Dou Y, Wang S J Med Chem. 2017 Jun 22;60(12):4818-4839. doi: 10.1021/acs.jmedchem.6b01796. Epub, 2017 Jun 12. PMID:28603984<ref>PMID:28603984</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4gmb" style="background-color:#fffaf0;"></div>
==See Also==
==See Also==
*[[WD-repeat protein 3D structures|WD-repeat protein 3D structures]]
*[[WD-repeat protein 3D structures|WD-repeat protein 3D structures]]
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Bernard D]]
[[Category: Bernard D]]

Revision as of 09:14, 15 November 2023

Crystal structure of human WD repeat domain 5 with compound MM-402

PDB ID 4gmb

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