5EX0: Crystal Structure Of Human Smyd3 In Complex With A Map3k2 Peptide

Citation:
Abstract
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.
PDB ID: 5EX0Download
MMDB ID: 137297
PDB Deposition Date: 2015/11/23
Updated in MMDB: 2017/10
Experimental Method:
x-ray diffraction
Resolution: 2.7  Å
Source Organism:
Similar Structures:
Biological Unit for 5EX0: dimeric; determined by author and by software (PISA)
Molecular Components in 5EX0
Label Count Molecule
Proteins (2 molecules)
1
Histone-lysine N-methyltransferase Smyd3(Gene symbol: SMYD3)
Molecule annotation
1
Map3k2 Peptide
Molecule annotation
Chemicals (6 molecules)
1
3
2
1
3
2
* Click molecule labels to explore molecular sequence information.

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