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PDBsum entry 4ia9
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Transcription
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PDB id
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4ia9
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PDB id:
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| Name: |
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Transcription
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Title:
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Crystal structure of human wd repeat domain 5 in complex with 2- chloro-4-fluoro-3-methyl-n-[2-(4-methylpiperazin-1-yl)-5- nitrophenyl]benzamide
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Structure:
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Wd repeat-containing protein 5. Chain: a. Synonym: bmp2-induced 3-kb gene protein. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: wdr5, big3. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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1.66Å
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R-factor:
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0.178
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R-free:
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0.210
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Authors:
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A.Dong,L.Dombrovski,Y.Bolshan,M.Getlik,W.Tempel,E.Kuznetsova, G.A.Wasney,T.Hajian,G.Poda,K.T.Nguyen,M.Schapira,P.J.Brown,R.Al- Awar,C.Bountra,C.H.Arrowsmith,A.M.Edwards,D.Smil,M.Vedadi,H.Wu, Structural Genomics Consortium (Sgc)
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Key ref:
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Y.Bolshan
et al.
(2013).
Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction.
ACS Med Chem Lett,
4,
353-357.
PubMed id:
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Date:
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06-Dec-12
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Release date:
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26-Dec-12
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PROCHECK
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Headers
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References
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P61964
(WDR5_HUMAN) -
WD repeat-containing protein 5 from Homo sapiens
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Seq:
Struc:
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334 a.a.
305 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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ACS Med Chem Lett
4:353-357
(2013)
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PubMed id:
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Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction.
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Y.Bolshan,
M.Getlik,
E.Kuznetsova,
G.A.Wasney,
T.Hajian,
G.Poda,
K.T.Nguyen,
H.Wu,
L.Dombrovski,
A.Dong,
G.Senisterra,
M.Schapira,
C.H.Arrowsmith,
P.J.Brown,
R.Al-Awar,
M.Vedadi,
D.Smil.
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ABSTRACT
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The WD40-repeat protein WDR5 plays a critical role in maintaining the integrity
of MLL complexes and fully activating their methyltransferase function. MLL
complexes, the trithorax-like family of SET1 methyltransferases, catalyze
trimethylation of lysine 4 on histone 3, and they have been widely implicated in
various cancers. Antagonism of WDR5 and MLL subunit interaction by small
molecules has recently been presented as a practical way to inhibit activity of
the MLL1 complex, and N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl)
benzamides were reported as potent and selective antagonists of such an
interaction. Here, we describe the protein crystal structure guided optimization
of prototypic compound 2 (K dis = 7 μM), leading to identification of more
potent antagonist 47 (K dis = 0.3 μM).
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