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AuthorThirumal Kumar, D
AuthorUdhaya Kumar, S
AuthorNishaat Laeeque, Ahmed Shaikh
AuthorApurva Abhay, Shivalkar
AuthorBithia, R
AuthorMagesh, R.
AuthorKumar, Maignana
AuthorZayed, Hatem
AuthorGeorge Priya Doss, C
Available date2020-03-22T08:44:46Z
Publication Date2020-02-01
Publication NameAdvances in Protein Chemistry and Structural Biology
Identifierhttp://dx.doi.org/10.1016/bs.apcsb.2019.11.005
CitationKumar, Thirumal Kumar. "Chapter Nine - Computational model to analyze and characterize the functional mutations of NOD2 protein causing inflammatory disorder – Blau syndrome" , voulme 120, 2020, page 379-408
ISSN1876-1623
URIhttp://hdl.handle.net/10576/13473
AbstractBlau syndrome (BS), which affects the eyes, skin, and joints, is an autosomal dominant genetic inflammatory disorder. BS is caused by mutations in the NOD2 gene. However, there are no direct treatments, and treatment with conventional anti-inflammatory drugs such as adrenal glucocorticoids, anti-metabolites, and biological agents such as anti-TNF and infliximab have all been attempted with varying degrees of success. In this study, we tried to identify all the reported mutations in the NOD2 protein that cause BS. Collectively, 114 missense mutations were extracted from the UniProt, ClinVar, and HGMD databases. The mutations were further subjected to pathogenic, stability, and conservation analyses. According to these computational analyses, six missense mutations (R334Q, R334W, E383G, E383K, R426H, and T605P) were found to be highly deleterious, destabilizing, and positioned in the conserved position. ADP to ATP conversion plays a crucial role in switching the closed-form of NOD2 protein to the open-form, thus activating the protein. Accordingly, the mutations in the ADP binding sites have received more attention in comparison to the mutations in the non-ADP binding positions. Interestingly, the W490L mutation is positioned in the ADP binding site and exhibits highly deleterious and destabilizing properties. Additionally, W490L was also found to be conserved, with a ConSurf score of 7. Therefore, we further performed homology modeling to determine the 3D structure of native NOD2 and the W490L mutant. Molecular docking analysis was carried out to understand the change in the interaction of ADP with the NOD2 protein. We observed that ADP had a stronger interaction with the native NOD2 protein compared to the W490L mutant. Finally, ADP complexed with native NOD2 and W490L mutant were subjected to molecular dynamics simulations, and the trajectories were analyzed. In the simulations, we observed decreased deviation and fluctuations in native NOD2, whereas decreased compactness and inter- and intramolecular hydrogen bonds were observed in the W490L mutant. This study is expected to serve as a platform for developing targeted drug therapy for BS.
Languageen
PublisherElsevier
SubjectBlau syndrome
Inflammatory disorder
Molecular docking
Molecular dynamics
NOD2 protein
TitleComputational model to analyze and characterize the functional mutations of NOD2 protein causing inflammatory disorder - Blau syndrome.
TypeArticle
Pagination379-408
Volume Number120
ESSN1876-1631


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