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• W2988974322 abstract "SMYD3, a SET and MYND domain containing lysine methyltransferase, catalyzes the transfer of the methyl group from a methyl donor onto the Nε group of a lysine residue in the substrate protein. Methylation of MAP3 kinase kinase (MAP3K2) by SMYD3 has been implicated in Ras-driven tumorigenesis. The crystal structure of SMYD3 in complex with MAP3K2 peptide reveals a shallow hydrophobic pocket (P-2), which accommodates the binding of a phenylalanine residue at the -2 position of the substrate (F258) is a crucial determinant of substrate specificity of SMYD3. To better understand the substrate preference of SMYD3 at the -2 position, molecular dynamics (MD) simulations and the MM/GBSA method were performed on the crystal structure of SMYD3-MAP3K2 complex (PDB: 5EX0) after substitution of F258 residue of MAP3K2 to each of the other 19 natural residues, respectively. Binding free energy calculations reveal that the P-2 pocket prefers an aromatic hydrophobic group and none of the substitutions behave better than the wild-type phenylalanine residue does. Furthermore, we investigated the structure-activity relationships (SAR) of a series of non-natural phenylalanine derivative substitutions at the -2 position and found that quite a few modifications on the sidechain of F258 residue could strengthen its binding to the P-2 pocket of SMYD3. These explorations provide insights into developing novel SMYD3 inhibitors with high potency and high selectivity against MAP3K2 and cancer." @default.
• W2988974322 created "2019-11-22" @default.
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• W2988974322 date "2019-11-12" @default.
• W2988974322 modified "2023-10-16" @default.
• W2988974322 title "Exploration of the Substrate Preference of Lysine Methyltransferase SMYD3 by Molecular Dynamics Simulations" @default.
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• W2988974322 doi "https://doi.org/10.1021/acsomega.9b01842" @default.
• W2988974322 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6881823" @default.
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