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PDBsum entry 5mw3
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PDB id:
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Transferase
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Title:
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Crystal structure of dot1l in complex with inhibitor cpd1 [n6-(2,6- dichlorophenyl)-n6-(pent-2-yn-1-yl)quinoline-4,6-diamine] and inhibitor cpd2 [(r)-1-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3- amine]
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Structure:
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Histone-lysine n-methyltransferase, h3 lysine-79 specific. Chain: a, b. Synonym: dot1-like protein,histone h3-k79 methyltransferase,h3-k79- hmtase,lysine n-methyltransferase 4. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: dot1l, kiaa1814, kmt4. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.09Å
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R-factor:
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0.176
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R-free:
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0.193
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Authors:
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C.Be,E.Koch,C.Gaul,F.Stauffer,H.Moebitz,C.Scheufler
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Key ref:
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H.Möbitz
et al.
(2017).
Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach.
Acs Med Chem Lett,
8,
338-343.
PubMed id:
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Date:
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18-Jan-17
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Release date:
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22-Mar-17
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PROCHECK
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Headers
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References
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Q8TEK3
(DOT1L_HUMAN) -
Histone-lysine N-methyltransferase, H3 lysine-79 specific from Homo sapiens
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Seq:
Struc:
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1537 a.a.
319 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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Enzyme class:
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E.C.2.1.1.360
- [histone H3]-lysine(79) N-trimethyltransferase.
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Reaction:
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L-lysyl79-[histone H3] + 3 S-adenosyl-L-methionine = N6,N6,N6- trimethyl-L-lysyl79-[histone H3] + 3 S-adenosyl-L-homocysteine + 3 H+
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L-lysyl(79)-[histone H3]
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+
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3
×
S-adenosyl-L-methionine
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=
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N(6),N(6),N(6)- trimethyl-L-lysyl(79)-[histone H3]
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+
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3
×
S-adenosyl-L-homocysteine
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+
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3
×
H(+)
Bound ligand (Het Group name = )
matches with 44.83% similarity
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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Acs Med Chem Lett
8:338-343
(2017)
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PubMed id:
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Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach.
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H.Möbitz,
R.Machauer,
P.Holzer,
A.Vaupel,
F.Stauffer,
C.Ragot,
G.Caravatti,
C.Scheufler,
C.Fernandez,
U.Hommel,
R.Tiedt,
K.S.Beyer,
C.Chen,
H.Zhu,
C.Gaul.
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ABSTRACT
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Misdirected catalytic activity of histone methyltransferase Dot1L is believed to
be causative for a subset of highly aggressive acute leukemias. Targeting the
catalytic domain of Dot1L represents a potential therapeutic approach for these
leukemias. In the context of a comprehensive Dot1L hit finding strategy, a
knowledge-based virtual screen of the Dot1L SAM binding pocket led to the
discovery of 2, a non-nucleoside fragment mimicking key interactions of SAM
bound to Dot1L. Fragment linking of 2 and 3, an induced back pocket binder
identified in earlier studies, followed by careful ligand optimization led to
the identification of 7, a highly potent, selective and structurally novel Dot1L
inhibitor.
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Links
