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PDBsum entry 5ex3
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PDB id:
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Transferase
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Title:
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Crystal structure of human smyd3 in complex with a vegfr1 peptide
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Structure:
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Histone-lysine n-methyltransferase smyd3. Chain: a. Synonym: set and mynd domain-containing protein 3,zinc finger mynd domain-containing protein 1. Engineered: yes. Mutation: yes. Vegfr1 peptide. Chain: d. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: smyd3, zmynd1, znfn3a1. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 9606
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Resolution:
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2.41Å
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R-factor:
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0.187
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R-free:
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0.223
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Authors:
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Q.Qiao,W.Fu,N.Liu,M.Wang,J.Min,B.Zhu,R.M.Xu,N.Yang
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Key ref:
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W.Fu
et al.
(2016).
Structural Basis for Substrate Preference of SMYD3, a SET Domain-containing Protein Lysine Methyltransferase.
J Biol Chem,
291,
9173-9180.
PubMed id:
DOI:
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Date:
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23-Nov-15
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Release date:
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09-Mar-16
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PROCHECK
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Headers
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References
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Q9H7B4
(SMYD3_HUMAN) -
Histone-lysine N-methyltransferase SMYD3 from Homo sapiens
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Seq:
Struc:
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428 a.a.
428 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 2 residue positions (black
crosses)
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Enzyme class:
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E.C.2.1.1.354
- [histone H3]-lysine(4) N-trimethyltransferase.
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Reaction:
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L-lysyl4-[histone H3] + 3 S-adenosyl-L-methionine = N6,N6,N6- trimethyl-L-lysyl4-[histone H3] + 3 S-adenosyl-L-homocysteine + 3 H+
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L-lysyl(4)-[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(4)-[histone H3]
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+
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3
×
S-adenosyl-L-homocysteine
Bound ligand (Het Group name = )
corresponds exactly
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+
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3
×
H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Biol Chem
291:9173-9180
(2016)
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PubMed id:
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Structural Basis for Substrate Preference of SMYD3, a SET Domain-containing Protein Lysine Methyltransferase.
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W.Fu,
N.Liu,
Q.Qiao,
M.Wang,
J.Min,
B.Zhu,
R.M.Xu,
N.Yang.
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ABSTRACT
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SMYD3 is a SET domain-containing N-lysine methyltransferase associated with
multiple cancers. Its reported substrates include histones (H3K4 and H4K5),
vascular endothelial growth factor receptor 1 (VEGFR1 Lys(831)) and MAP3 kinase
kinase (MAP3K2 Lys(260)). To reveal the structural basis for substrate
preference and the catalytic mechanism of SMYD3, we have solved its co-crystal
structures with VEGFR1 and MAP3K2 peptides. Our structural and biochemical
analyses show that MAP3K2 serves as a robust substrate of SMYD3 because of the
presence of a phenylalanine residue at the -2 position. A shallow hydrophobic
pocket on SMYD3 accommodates the binding of the phenylalanine and promotes
efficient catalytic activities of SMYD3. By contrast, SMYD3 displayed a weak
activity toward a VEGFR1 peptide, and the location of the acceptor lysine in the
folded kinase domain of VEGFR1 requires drastic conformational rearrangements
for juxtaposition of the acceptor lysine with the enzymatic active site. Our
results clearly revealed structural determinants for the substrate preference of
SMYD3 and provided mechanistic insights into lysine methylation of MAP3K2. The
knowledge should be useful for the development of SMYD3 inhibitors in the fight
against MAP3K2 and Ras-driven cancer.
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Links
