title: Explaining the autoinhibition of the SMYD enzyme family: A theoretical study.
abstract: The SMYD enzymes (SMYD1-5) are lysine methyltransferases that have diverse biological functions including gene expression and regulation of skeletal and cardiac muscle development and function. Recently, they have gained more attention as potential drug targets because of their involvement in cardiovascular diseases and in the progression of different cancer types. Their activity has been suggested to be regulated by a posttranslational mechanism and by autoinhibition. The later relies on a hinge-like movement of the N- and C-lobes to adopt an open or closed conformation, consequently, determining the accessibility of the active site and substrate specificity. In this study we aim to investigate and explain the possibility of the regulatory autoinhibition process of the SMYD enzymes by a thorough computational exploration of their dynamic, energetic, and structural changes by using extended molecular dynamics simulations; normal mode analysis (NMA); and energy correlations. Three SMYD models (SMYD1-3) were used in this study. Our results showed an obvious hinge-like motion between the N- and C-lobes. Also, we identified interaction energy pathways within the 3D structures of the proteins, and hot spots on their surfaces that could be of particular importance for the regulation of their activities via allosteric means. These results can help in a better understanding of the nature of these promising drug targets; and in designing selective drugs that can interfere with (inhibit) the function of a specific SMYD member by disrupting its dynamical and conformational behaviour without disrupting the function of the entire SMYD proteins.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan. Electronic address: nashari@just.edu.jo.
authors.forename: Nizar A
authors.initials: NA
authors.lastname: Al-Shar'i
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan. Electronic address: smalnabulsi@just.edu.jo.
authors.forename: Soraya M
authors.initials: SM
authors.lastname: Alnabulsi
mesh_terms: D018360:Crystallography, X-Ray; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D005810:Multigene Family; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D008780:Methyltransferases
keywords: Autoinhibition; Energy correlation; MD simulations; Normal mode analysis; SMYD family