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PDBsum entry 5ij8
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Transferase/transferase inhibitor
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PDB id
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5ij8
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Contents |
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464 a.a.
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358 a.a.
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128 a.a.
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References listed in PDB file
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Key reference
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Title
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Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance.
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Authors
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A.Brooun,
K.S.Gajiwala,
Y.L.Deng,
W.Liu,
B.Bolaños,
P.Bingham,
Y.A.He,
W.Diehl,
N.Grable,
P.P.Kung,
S.Sutton,
K.A.Maegley,
X.Yu,
A.E.Stewart.
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Ref.
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Nat Commun, 2016,
7,
11384.
[DOI no: ]
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PubMed id
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Abstract
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Polycomb repressive complex 2 (PRC2) mediates gene silencing through chromatin
reorganization by methylation of histone H3 lysine 27 (H3K27). Overexpression of
the complex and point mutations in the individual subunits of PRC2 have been
shown to contribute to tumorigenesis. Several inhibitors of the PRC2 activity
have shown efficacy in EZH2-mutated lymphomas and are currently in clinical
development, although the molecular basis of inhibitor recognition remains
unknown. Here we report the crystal structures of the inhibitor-bound wild-type
and Y641N PRC2. The structures illuminate an important role played by a stretch
of 17 residues in the N-terminal region of EZH2, we call the activation loop, in
the stimulation of the enzyme activity, inhibitor recognition and the potential
development of the mutation-mediated drug resistance. The work presented here
provides new avenues for the design and development of next-generation PRC2
inhibitors through establishment of a structure-based drug design platform.
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