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PDBsum entry 4eqz
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Transferase/transferase inhibitor
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PDB id
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4eqz
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References listed in PDB file
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Key reference
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Title
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Catalytic site remodelling of the dot1l methyltransferase by selective inhibitors.
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Authors
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W.Yu,
E.J.Chory,
A.K.Wernimont,
W.Tempel,
A.Scopton,
A.Federation,
J.J.Marineau,
J.Qi,
D.Barsyte-Lovejoy,
J.Yi,
R.Marcellus,
R.E.Iacob,
J.R.Engen,
C.Griffin,
A.Aman,
E.Wienholds,
F.Li,
J.Pineda,
G.Estiu,
T.Shatseva,
T.Hajian,
R.Al-Awar,
J.E.Dick,
M.Vedadi,
P.J.Brown,
C.H.Arrowsmith,
J.E.Bradner,
M.Schapira.
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Ref.
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Nat Commun, 2012,
3,
1288.
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PubMed id
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Abstract
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Selective inhibition of protein methyltransferases is a promising new approach
to drug discovery. An attractive strategy towards this goal is the development
of compounds that selectively inhibit binding of the cofactor,
S-adenosylmethionine, within specific protein methyltransferases. Here we report
the three-dimensional structure of the protein methyltransferase DOT1L bound to
EPZ004777, the first S-adenosylmethionine-competitive inhibitor of a protein
methyltransferase with in vivo efficacy. This structure and those of four new
analogues reveal remodelling of the catalytic site. EPZ004777 and a brominated
analogue, SGC0946, inhibit DOT1L in vitro and selectively kill mixed lineage
leukaemia cells, in which DOT1L is aberrantly localized via interaction with an
oncogenic MLL fusion protein. These data provide important new insight into
mechanisms of cell-active S-adenosylmethionine-competitive protein
methyltransferase inhibitors, and establish a foundation for the further
development of drug-like inhibitors of DOT1L for cancer therapy.
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