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Structural Analysis of SMYD3 Lysine Methyltransferase for the Development of Competitive and Specific Enzyme Inhibitors.

ABSTRACT: Lysine methylation is among the key posttranslational modifications to histones that contribute to epigenetic regulation. SMYD3 is a lysine methyltransferase that is essential for the proliferation of a range of tumorigenic cells. The findings that SMYD3 is significantly upregulated in most colorectal carcinomas, hepatocellular carcinomas, and breast cell carcinomas support a model in which its aberrant expression modifies established patterns of gene expression, ultimately driving unrestrained proliferation. Herein, we dissect the unique structural features of SMYD3 relative to other SET enzymes, with an emphasis on the implications for selective design of therapeutics for the clinical management of cancer. Further, we illustrate the ability of inhibitors targeting the SET domain of SMYD3 to reduce the viability of colorectal and lung carcinoma cells.

SUBMITTER: Jarrell DK

PROVIDER: S-EPMC8788566 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Structural Analysis of SMYD3 Lysine Methyltransferase for the Development of Competitive and Specific Enzyme Inhibitors.

Jarrell Dillon K DK Hassell Kelly N KN Alshiraihi Ilham I Crans Debbie C DC Brown Mark A MA

Diseases (Basel, Switzerland) 20211229 1

Lysine methylation is among the key posttranslational modifications to histones that contribute to epigenetic regulation. SMYD3 is a lysine methyltransferase that is essential for the proliferation of a range of tumorigenic cells. The findings that SMYD3 is significantly upregulated in most colorectal carcinomas, hepatocellular carcinomas, and breast cell carcinomas support a model in which its aberrant expression modifies established patterns of gene expression, ultimately driving unrestrained ...[more]

PMID: 35076487

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Structural Basis for Substrate Preference of SMYD3, a SET Domain-containing Protein Lysine Methyltransferase.

Project description: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.

| S-EPMC4861483 | biostudies-literature

Discovery of an Allosteric Ligand Binding Site in SMYD3 Lysine Methyltransferase.

Project description:SMYD3 is a multifunctional epigenetic enzyme with lysine methyltransferase activity and various interaction partners. It is implicated in the pathophysiology of cancers but with an unclear mechanism. To discover tool compounds for clarifying its biochemistry and potential as a therapeutic target, a set of drug-like compounds was screened in a biosensor-based competition assay. Diperodon was identified as an allosteric ligand; its R and S enantiomers were isolated, and their affinities to SMYD3 were determined (KD =42 and 84 μM, respectively). Co-crystallization revealed that both enantiomers bind to a previously unidentified allosteric site in the C-terminal protein binding domain, consistent with its weak inhibitory effect. No competition between diperodon and HSP90 (a known SMYD3 interaction partner) was observed although SMYD3-HSP90 binding was confirmed (KD =13 μM). Diperodon clearly represents a novel starting point for the design of tool compounds interacting with a druggable allosteric site, suitable for the exploration of noncatalytic SMYD3 functions and therapeutics with new mechanisms of action.

| S-EPMC8248052 | biostudies-literature

Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3.

Project description:SMYD3 is a histone methyltransferase that regulates gene transcription, and its overexpression is associated with multiple human cancers. A novel class of tetrahydroacridine compounds which inhibit SMYD3 through a covalent mechanism of action is identified. Optimization of these irreversible inhibitors resulted in the discovery of 4-chloroquinolines, a new class of covalent warheads. Tool compound 29 exhibits high potency by inhibiting SMYD3's enzymatic activity and showing antiproliferative activity against HepG2 in 3D cell culture. Our findings suggest that covalent inhibition of SMYD3 may have an impact on SMYD3 biology by affecting expression levels, and this warrants further exploration.

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Protein lysine methyltransferase SMYD3 is involved in tumorigenesis through regulation of HER2 homodimerization.

Project description:HER2 is a receptor tyrosine kinase, which is amplified and overexpressed in a subset of human cancers including breast and gastric cancers, and is indicated in its involvement in progression of cancer. Although its specific ligand(s) has not been detected, HER2 homodimerization, which is critical for its activation, is considered to be dependent on its expression levels. Here, we demonstrate a significant role of HER2 methylation by protein lysine methyltransferase SMYD3 in HER2 homodimerization. We found that SMYD3 trimethylates HER2 protein at lysine 175. HER2 homodimerization was enhanced in the presence of SMYD3, and substitution of lysine 175 of HER2 with alanine (HER2-K175A) reduced the formation of HER2 homodimers. Furthermore, HER2-K175A revealed lower level of autophosphorylation than wild-type HER2. We also identified that knockdown of SMYD3 attenuated this autophosphorylation in breast cancer cells. Our results imply that SMYD3-mediated methylation of HER2 at Lysine 175 may regulate the formation of HER2 homodimer and subsequent autophosphorylation and suggest that the SMYD3-mediated methylation pathway seems to be a good target for development of novel anti-cancer therapy.

| S-EPMC5504314 | biostudies-literature

Exploration of the Substrate Preference of Lysine Methyltransferase SMYD3 by Molecular Dynamics Simulations.

Project description: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.

| S-EPMC6881823 | biostudies-literature

Correction to "Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3".

Project description:[This corrects the article DOI: 10.1021/acsmedchemlett.9b00170.].

| S-EPMC6691561 | biostudies-literature

The Lysine Methylase SMYD3 Modulates Mesendodermal Commitment during Development.

Project description:SMYD3 (SET and MYND domain containing protein 3) is a methylase over-expressed in cancer cells and involved in oncogenesis. While several studies uncovered key functions for SMYD3 in cancer models, the SMYD3 role in physiological conditions has not been fully elucidated yet. Here, we dissect the role of SMYD3 at early stages of development, employing mouse embryonic stem cells (ESCs) and zebrafish as model systems. We report that SMYD3 depletion promotes the induction of the mesodermal pattern during in vitro differentiation of ESCs and is linked to an upregulation of cardiovascular lineage markers at later stages. In vivo, smyd3 knockdown in zebrafish favors the upregulation of mesendodermal markers during zebrafish gastrulation. Overall, our study reveals that SMYD3 modulates levels of mesendodermal markers, both in development and in embryonic stem cell differentiation.

| S-EPMC8157265 | biostudies-literature

Structural and functional profiling of the human histone methyltransferase SMYD3.

Project description:The SET and MYND Domain (SMYD) proteins comprise a unique family of multi-domain SET histone methyltransferases that are implicated in human cancer progression. Here we report an analysis of the crystal structure of the full length human SMYD3 in a complex with an analog of the S-adenosyl methionine (SAM) methyl donor cofactor. The structure revealed an overall compact architecture in which the "split-SET" domain adopts a canonical SET domain fold and closely assembles with a Zn-binding MYND domain and a C-terminal superhelical 9 α-helical bundle similar to that observed for the mouse SMYD1 structure. Together, these structurally interlocked domains impose a highly confined binding pocket for histone substrates, suggesting a regulated mechanism for its enzymatic activity. Our mutational and biochemical analyses confirm regulatory roles of the unique structural elements both inside and outside the core SET domain and establish a previously undetected preference for trimethylation of H4K20.

| S-EPMC3136521 | biostudies-literature

Structural and functional profiling of the human histone methyltransferase SMYD3.

| S-EPMC3136521 | biostudies-literature

Histone lysine methyltransferase SMYD3 promotes oral squamous cell carcinoma tumorigenesis via H3K4me3-mediated HMGA2 transcription.

Project description:BackgroundEpigenetic dysregulation is essential to the tumorigenesis of oral squamous cell carcinoma (OSCC). SET and MYND domain-containing protein 3 (SMYD3), a histone lysine methyltransferase, is implicated in gene transcription regulation and tumor development. However, the roles of SMYD3 in OSCC initiation are not fully understood. The present study investigated the biological functions and mechanisms involved in the SMYD3-mediated tumorigenesis of OSCC utilizing bioinformatic approaches and validation assays with the aim of informing the development of targeted therapies for OSCC.Results429 chromatin regulators were screened by a machine learning approach and aberrant expression of SMYD3 was found to be closely associated with OSCC formation and poor prognosis. Data profiling of single-cell and tissue demonstrated that upregulated SMYD3 significantly correlated with aggressive clinicopathological features of OSCC. Alterations in copy number and DNA methylation patterns may contribute to SMYD3 overexpression. Functional experimental results suggested that SMYD3 enhanced cancer cell stemness and proliferation in vitro and tumor growth in vivo. SMYD3 was observed to bind to the High Mobility Group AT-Hook 2 (HMGA2) promoter and elevated tri-methylation of histone H3 lysine 4 at the corresponding site was responsible for transactivating HMGA2. SMYD3 also was positively linked to HMGA2 expression in OSCC samples. Furthermore, treatment with the SMYD3 chemical inhibitor BCI-121 exerted anti-tumor effects.ConclusionsHistone methyltransferase activity and transcription-potentiating function of SMYD3 were found to be essential for tumorigenesis and the SMYD3-HMGA2 is a potential therapeutic target in OSCC.

| S-EPMC10223939 | biostudies-literature

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