5EX3

Crystal structure of human SMYD3 in complex with a VEGFR1 peptide

Summary for 5EX3

• Entry DOI: 10.2210/pdb5ex3/pdb
• Related: 5EX0
• Descriptor: Histone-lysine N-methyltransferase SMYD3, VEGFR1 peptide, ZINC ION, ... (6 entities in total)
• Functional Keywords: set domain, methylation, chromatin, cancer, transferase
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm : Q9H7B4
• Total number of polymer chains: 2
• Total formula weight: 51785.10

Authors

Qiao, Q.,Fu, W.,Liu, N.,Wang, M.,Min, J.,Zhu, B.,Xu, R.M.,Yang, N. (deposition date: 2015-11-23, release date: 2016-03-09, Last modification date: 2017-10-18)

Primary citation

Fu, W.,Liu, N.,Qiao, Q.,Wang, M.,Min, J.,Zhu, B.,Xu, R.M.,Yang, N.
Structural Basis for Substrate Preference of SMYD3, a SET Domain-containing Protein Lysine Methyltransferase
J.Biol.Chem., 291:9173-9180, 2016

PubMed 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.

PubMed: 26929412
DOI: 10.1074/jbc.M115.709832

Experimental method

X-RAY DIFFRACTION (2.408 Å)