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.

Post-Translational Modifications of BRD4: Therapeutic Targets for Tumor

“…Lysine methylation, a key, dynamic posttranslational modification that regulates protein stability and function, is regulated by lysine methyltransferase and lysine demethylase (95)(96)(97)(98). The abnormal expression of methyltransferase in many tumor types has been proven to be related to tumorigenesis and development, which has become the focus of anticancer research (98)(99)(100). These enzymes are now considered potential therapeutic targets, and they may be used as potential anticancer drugs in the clinic (100,101).…”

Targeting Epigenetic Changes Mediated by Members of the SMYD Family of Lysine Methyltransferases

“…Structural information is available for SMYD1, SMYD2, and SMYD3 proteins which share clear similarities [ 29 ] and, in general, there is a high degree of homology in their gene sequences ( Figure 1 ) [ 30 , 31 , 32 ]. Like SMYD1 and SMYD2 [ 9 ], SMYD3 proteins consist of six sub-domains, N-SET, MYND, I-SET, core-SET (also referred to s C-SET or (S)ET in the literature), post-SET, and C-terminus domains (also referred to as C-lobe or CTD).…”

“…Like SMYD1 and SMYD2 [ 9 ], SMYD3 proteins consist of six sub-domains, N-SET, MYND, I-SET, core-SET (also referred to s C-SET or (S)ET in the literature), post-SET, and C-terminus domains (also referred to as C-lobe or CTD). The SMYD3 N-SET domain is highly conserved with other SET proteins found in humans, plants, yeast, and viruses [ 24 , 29 , 32 ]. The SYMD3 C-terminus domain is the least conserved among SMYD proteins, with no significant similarity to other known protein domains.…”

“…Interestingly, a RUBICO_LSMT domain referred to as I-SET has been identified in the SMYD3 protein. This I-SET domain is composed of four beta sheets linked by a hairpin, between beta-1 and beta-2, and a loop between beta-2 and beta-3 [ 29 , 32 ]. SMYD3’s MYND domain binds Zn 2+ in a zinc-finger domain that links its Rubisco-LSMT, SET-N, and SET-C domains.…”

“…SMYD3’s MYND domain binds Zn 2+ in a zinc-finger domain that links its Rubisco-LSMT, SET-N, and SET-C domains. The protein binding pocket is near the SET-C and the post-C domains [ 29 , 32 ].…”