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PDBsum entry 5t5g
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Transferase/transferase inhibitor
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PDB id
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5t5g
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References listed in PDB file
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Key reference
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Title
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Structure-Based design of a covalent inhibitor of the set domain-Containing protein 8 (setd8) lysine methyltransferase.
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Authors
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K.V.Butler,
A.Ma,
W.Yu,
F.Li,
W.Tempel,
N.Babault,
F.Pittella-Silva,
J.Shao,
J.Wang,
M.Luo,
M.Vedadi,
P.J.Brown,
C.H.Arrowsmith,
J.Jin.
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Ref.
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J Med Chem, 2016,
59,
9881-9889.
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PubMed id
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Abstract
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Selective inhibitors of protein lysine methyltransferases, including SET
domain-containing protein 8 (SETD8), are highly desired, as only a fraction of
these enzymes are associated with high-quality inhibitors. From our previously
discovered SETD8 inhibitor, we developed a more potent analog and solved a
cocrystal structure, which is the first crystal structure of SETD8 in complex
with a small-molecule inhibitor. This cocrystal structure allowed the design of
a covalent inhibitor of SETD8 (MS453), which specifically modifies a cysteine
residue near the inhibitor binding site, has an IC50 value of 804 nM,
reacts with SETD8 with near-quantitative yield, and is selective for SETD8
against 28 other methyltransferases. We also solved the crystal structure of the
covalent inhibitor in complex with SETD8. This work provides atomic-level
perspective on the inhibition of SETD8 by small molecules and will help identify
high-quality chemical probes of SETD8.
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