Structural Basis for Substrate Preference of SMYD3, a SET Domain-containing Protein Lysine Methyltransferase
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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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Residues D255-Y257 of SMYD3 are located within 3.6 angstroms of an EPZ031686 analog in the SMYD3 co-crystal structure, and Y257 interacts with the methylated lysine in substrate co-crystal structures.
“These residues are located within 3.6 angstroms of an EPZ031686 analog in the SMYD3 co-crystal structure (Fig. 4c), and Y257 specifically has been found to interact with the methylated lysine in substrate co-crystal structures39.”
From Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs (2019) · cites this paper as [39]
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Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs
Wang, Y., Dix, M. M., Bianco, G., Remsberg, J. R., Lee, H.-Y., Kalocsay, M., Gygi, S. P., Forli, S., Vite, G., Lawrence, R. M., et al. (2019) · Nature Chemistry · doi:10.1038/s41557-019-0351-5 · Cited by 179 · see citing works
- Authors
- Fu, W., Liu, N., Qiao, Q., Wang, M., Min, J., Zhu, B., Xu, R.-M., & Yang, N.
- Affiliations
- Chinese Academy of Sciences (CN)
- University of Toronto (CA)
- Corresponding author
- Zhu, Bing
- Xu, Rui-Ming
- Yang, Na
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 291
- Issue
- 17
- Pages
- 9173-9180
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4861483
- OpenAlex
- W2289047474
- Cited by
- 38
- References
- 36
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 1 · 2022: 5 · 2021: 3 · 2020: 3 · 2019: 9 · 2018: 3 · 2017: 3 · 2016: 3
- FWCI
- 3.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- SMYD3, SET domain, substrate preference, MAP3K2, VEGFR1, lysine methylation, co-crystal structure, hydrophobic pocket, catalytic mechanism, RAS-driven cancers
- MeSH terms
- Catalysis, Humans, Methylation, Histone-Lysine N-Methyltransferase, Structure-Activity Relationship, Substrate Specificity, Crystallography, X-Ray, Catalytic Domain, MAP Kinase Kinase Kinases, Vascular Endothelial Growth Factor Receptor-1, MAP Kinase Kinase Kinase 2
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