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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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PDB id:
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| Name: |
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Transferase/transferase inhibitor
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Title:
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Human setd8 in complex with ms2177
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Structure:
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N-lysine methyltransferase kmt5a. Chain: a. Fragment: unp residues 234-380. Synonym: h4-k20-hmtase kmt5a,histone-lysine n-methyltransferase kmt5a,lysine n-methyltransferase 5a,lysine-specific methylase 5a, pr/set domain-containing protein 07,pr/set07,set domain-containing protein 8. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: kmt5a, prset7, set07, set8, setd8. Expressed in: escherichia coli. Expression_system_taxid: 511693.
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Resolution:
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2.10Å
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R-factor:
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0.206
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R-free:
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0.227
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Authors:
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W.Yu,W.Tempel,N.Babault,A.Ma,K.V.Butler,J.Jin,C.H.Arrowsmith, C.Bountra,A.M.Edwards,P.J.Brown,Structural Genomics Consortium (Sgc)
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Key ref:
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K.V.Butler
et al.
(2016).
Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase.
J Med Chem,
59,
9881-9889.
PubMed id:
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Date:
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30-Aug-16
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Release date:
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28-Sep-16
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PROCHECK
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Headers
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References
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Q9NQR1
(KMT5A_HUMAN) -
N-lysine methyltransferase KMT5A from Homo sapiens
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Seq:
Struc:
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393 a.a.
143 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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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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Enzyme class 1:
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E.C.2.1.1.-
- ?????
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Enzyme class 2:
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E.C.2.1.1.361
- [histone H4]-lysine(20) N-methyltransferase.
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Reaction:
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L-lysyl20-[histone H4] + S-adenosyl-L-methionine = N6-methyl-L- lysyl20-[histone H4] + S-adenosyl-L-homocysteine + H+
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L-lysyl(20)-[histone H4]
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+
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S-adenosyl-L-methionine
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=
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N(6)-methyl-L- lysyl(20)-[histone H4]
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+
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S-adenosyl-L-homocysteine
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+
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H(+)
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Note, where more than one E.C. class is given (as above), each may
correspond to a different protein domain or, in the case of polyprotein
precursors, to a different mature protein.
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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J Med Chem
59:9881-9889
(2016)
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PubMed id:
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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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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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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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