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PDBsum entry 4fmu
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PDB id:
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Transferase
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Title:
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Crystal structure of methyltransferase domain of human set domain- containing protein 2 compound: pr-snf
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Structure:
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Histone-lysine n-methyltransferase setd2. Chain: a. Synonym: hif-1, huntingtin yeast partner b, huntingtin-interacting protein 1, hip-1, huntingtin-interacting protein b, lysine n- methyltransferase 3a, set domain-containing protein 2, hset2, p231hbp. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: setd2, hif1, hypb, kiaa1732, kmt3a, set2, hspc069. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.10Å
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R-factor:
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0.195
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R-free:
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0.235
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Authors:
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A.Dong,H.Zeng,G.Ibanez,W.Zheng,W.Tempel,C.Bountra,C.H.Arrowsmith, A.M.Edwards,P.J.Brown,J.Min,M.Luo,H.Wu,Structural Genomics Consortium (Sgc)
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Key ref:
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W.Zheng
et al.
(2012).
Sinefungin derivatives as inhibitors and structure probes of protein lysine methyltransferase SETD2.
J Am Chem Soc,
134,
18004-18014.
PubMed id:
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Date:
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18-Jun-12
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Release date:
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05-Sep-12
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PROCHECK
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Headers
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References
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Q9BYW2
(SETD2_HUMAN) -
Histone-lysine N-methyltransferase SETD2 from Homo sapiens
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Seq:
Struc:
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2564 a.a.
235 a.a.
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Key: |
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Secondary structure |
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CATH domain |
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Enzyme class 2:
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E.C.2.1.1.-
- ?????
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Enzyme class 3:
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E.C.2.1.1.359
- [histone H3]-lysine(36) N-trimethyltransferase.
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Reaction:
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L-lysyl36-[histone H3] + 3 S-adenosyl-L-methionine = N6,N6,N6- trimethyl-L-lysyl36-[histone H3] + 3 S-adenosyl-L-homocysteine + 3 H+
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L-lysyl(36)-[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(36)-[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(+)
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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 Am Chem Soc
134:18004-18014
(2012)
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PubMed id:
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Sinefungin derivatives as inhibitors and structure probes of protein lysine methyltransferase SETD2.
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W.Zheng,
G.Ibáñez,
H.Wu,
G.Blum,
H.Zeng,
A.Dong,
F.Li,
T.Hajian,
A.Allali-Hassani,
M.F.Amaya,
A.Siarheyeva,
W.Yu,
P.J.Brown,
M.Schapira,
M.Vedadi,
J.Min,
M.Luo.
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ABSTRACT
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Epigenetic regulation is involved in numerous physiological and pathogenic
processes. Among the key regulators that orchestrate epigenetic signaling are
over 50 human protein lysine methyltransferases (PKMTs). Interrogation of the
functions of individual PKMTs can be facilitated by target-specific PKMT
inhibitors. Given the emerging need for such small molecules, we envisioned an
approach to identify target-specific methyltransferase inhibitors by screening
privileged small-molecule scaffolds against diverse methyltransferases. In this
work, we demonstrated the feasibility of such an approach by identifying the
inhibitors of SETD2. N-propyl sinefungin (Pr-SNF) was shown to interact
preferentially with SETD2 by matching the distinct transition-state features of
SETD2's catalytically active conformer. With Pr-SNF as a structure probe, we
further revealed the dual roles of SETD2's post-SET loop in regulating substrate
access through a distinct topological reconfiguration. Privileged sinefungin
scaffolds are expected to have broad use as structure and chemical probes of
methyltransferases.
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