Analysis of Matrix Metalloproteinases 13(MMP-13) non-synonymous Single Nucleotide Variants (nsSNVs) in Osteoarthritis and Prediction of Druggable Binding Sites Using COSMIC
Journal Title: Saudi Journal of Medical and Pharmaceutical Sciences - Year 2017, Vol 3, Issue 11
Abstract
Abstract:Osteoarthritis (OA) is a degenerative joint disease characterized by progressive loss and damage of articular cartilage. Increased collagenase activity has a direct impact in the cleavage of type II collagen in osteoarthritis. Somatic mutations such as non-synonymous single nucleotide variants (nsSNVs) in coding regions have a role in the pathogenesis of a number of diseases including OA. Matrix metalloproteinase 13 (MMP-13) is a critical target gene in the progression of osteoarthritis. Liver injury and regeneration have both been linked to MMP-13 gene expression. Analysis of MMP-13 gene was conducted using online bioinformatics tool, COSMIC and nsSNVs contributing to possible accumulation events that leads to osteoarthritic phenotypes were identified. The most frequently occurring missense mutation was found to be p.T280M; threonine to methionine that showed gain in function. Moreover, to get insight into the effect of mutation on protein structure and drug binding, MMP-13 three-dimensional structure was analyzed through COSMIC 3D. Structural analyses revealed amino acid substitutions located in hemopexin (HPX) domain. Hemopexin domains are thought to be required in the activation of matrix metalloproteinases (MMPs) via increased activation of pro enzyme and thus, increased collagen hydrolysis. Therefore, there may be a possibility to modify enzyme activity through antagonist molecules targeted to such alternative enzyme domains. For this reason possible drug binding sites were also identified using COSMIC 3D. An understanding of the mechanisms of activation of procollagenases is important to prevent cartilage destruction and could be utilized for the rational design of novel MMP-13 inhibitors. Keywords:Osteoarthritis, collagenase 3, matrix metalloproteinase -13, non synonymous single nucleotide variants, COSMIC
Authors and Affiliations
Ambreen Faiyaz
Keywords
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