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AuthorThirumal Kumar, D
AuthorJudith, E
AuthorPriyadharshini Christy, J
AuthorSiva, R
AuthorTayubi, Iftikhar Aslam
AuthorChakraborty, Chiranjib
AuthorGeorge Priya Doss, C
AuthorZayed, Hatem
Available date2019-01-24T07:28:19Z
Publication Date2019-01-01
Publication NameAdvances in Protein Chemistry and Structural Biologyen_US
Identifierhttp://dx.doi.org/10.1016/bs.apcsb.2018.10.009
CitationThirumal Kumar D, Judith E, Priyadharshini Christy J, Siva R, Tayubi IA, Chakraborty C, George Priya Doss C, Zayed H. Computational and modeling approaches to understand the impact of the Fabry's disease causing mutation (D92Y) on the interaction with pharmacological chaperone 1-deoxygalactonojirimycin (DGJ). Adv Protein Chem Struct Biol. 2019;114:341-407. doi: 10.1016/bs.apcsb.2018.10.009
ISSN1876-1623
URIhttp://hdl.handle.net/10576/11285
AbstractFabry's disease (FD) is the second most commonly occurring lysosomal storage disorders (LSDs). The mutations in α-galactosidase A (GLA) protein were widely found to be causative for the Fabry's disease. These mutations result in alternate splicing methods that affect the stability and function of the protein. The mutations near the active site of the protein results in protein misfolding. In this study, we have retrieved the missense mutation data from the three public databases (NCBI, UniProt, and HGMD). We used multiple in silico tools to predict the pathogenicity and stability of these mutations. Mutations in the active sites (D92Y, C142Y, D170V, and D266N) of the protein were screened for the phenotyping analysis using SNPeffect 4.0. Mutant D92Y was predicted to increase the amyloid propensity as well as severely reduce the protein stability and the remaining mutations showed no significant results by SNPeffect 4.0. Protein dynamics simulations (PDS) were performed to understand the behavior of the proteins due to the mutations. The simulation results showed that the D92Y mutant was more severe (higher deviation, loss of intramolecular hydrogen bonds, and lower compactness) than the other protein mutants (C142Y, D170V, and D266N). Further, the action of pharmacological chaperone 1-deoxygalactonojirimycin (DGJ) over the severe mutation was studied using the molecular docking analysis. Chaperone DGJ, an iminosugar plays a convincing role in repairing the misfolded protein and helps the protein to achieve its normal function. From the molecular docking analysis, we observed that both the native protein and protein with D92Y mutation followed similar interaction patterns. Further, the docked complexes (native-DGJ and mutant-DGJ) were subjected to PDS analysis. From the simulation analysis, we observed that DGJ had shown the better effect on the protein with the D92Y mutation. This elucidates that DGJ can still be used as a promising chaperone to treat the FD caused by mutations of GLA protein.
Languageen
PublisherElsevier
SubjectD92Y
SubjectDGJ
SubjectFabry's disease
SubjectMolecular docking
SubjectMolecular dynamics
TitleComputational and modeling approaches to understand the impact of the Fabry's disease causing mutation (D92Y) on the interaction with pharmacological chaperone 1-deoxygalactonojirimycin (DGJ).
TypeBook chapter
Pagination341-407
Volume Number114
dc.identifier.essn 1876-1631


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