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PDBsum entry 4gm3
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Transcription/transcription inhibitor
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PDB id
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4gm3
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PDB id:
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| Name: |
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Transcription/transcription inhibitor
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Title:
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Crystal structure of human wd repeat domain 5 with compound mm-101
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Structure:
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Wd repeat-containing protein 5. Chain: a, b, c, d, e, f, g, h. Fragment: unp residues 22-334. Synonym: wdr5, bmp2-induced 3-kb gene protein. Engineered: yes. Mm-101. Chain: i, j, k, l, m, n, o, p. 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. Synthetic: yes
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Resolution:
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3.39Å
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R-factor:
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0.197
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R-free:
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0.226
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Authors:
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H.Karatas,E.C.Townsend,Y.Chen,D.Bernard,F.Cao,L.Liu,M.Lei,Y.Dou, S.Wang
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Key ref:
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H.Karatas
et al.
(2013).
High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction.
J Am Chem Soc,
135,
669-682.
PubMed id:
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Date:
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15-Aug-12
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Release date:
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31-Jul-13
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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.
304 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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J Am Chem Soc
135:669-682
(2013)
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PubMed id:
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High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction.
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H.Karatas,
E.C.Townsend,
F.Cao,
Y.Chen,
D.Bernard,
L.Liu,
M.Lei,
Y.Dou,
S.Wang.
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ABSTRACT
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Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4)
methyltransferase, and targeting the MLL1 enzymatic activity has been proposed
as a novel therapeutic strategy for the treatment of acute leukemia harboring
MLL1 fusion proteins. The MLL1/WDR5 protein-protein interaction is essential for
MLL1 enzymatic activity. In the present study, we designed a large number of
peptidomimetics to target the MLL1/WDR5 interaction based upon -CO-ARA-NH-, the
minimum binding motif derived from MLL1. Our study led to the design of
high-affinity peptidomimetics, which bind to WDR5 with K(i) < 1 nM and
function as potent antagonists of MLL1 activity in a fully reconstituted in
vitro H3K4 methyltransferase assay. Determination of co-crystal structures of
two potent peptidomimetics in complex with WDR5 establishes their structural
basis for high-affinity binding to WDR5. Evaluation of one such peptidomimetic,
MM-102, in bone marrow cells transduced with MLL1-AF9 fusion construct shows
that the compound effectively decreases the expression of HoxA9 and Meis-1, two
critical MLL1 target genes in MLL1 fusion protein mediated leukemogenesis.
MM-102 also specifically inhibits cell growth and induces apoptosis in leukemia
cells harboring MLL1 fusion proteins. Our study provides the first
proof-of-concept for the design of small-molecule inhibitors of the WDR5/MLL1
protein-protein interaction as a novel therapeutic approach for acute leukemia
harboring MLL1 fusion proteins.
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Links
