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== Function ==
== Function ==
[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>  
[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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== Publication Abstract from PubMed ==
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.
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>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
==See Also==

Latest revision as of 15:50, 14 March 2024

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

4gmb, resolution 2.78Å

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