Juvenile myelomonocytic leukemia (JMML) is an invasive myeloproliferative neoplasm and is a childhood disease with very high clinical lethality. The SHP2 is encoded by the PTPN11 gene, which is a nonreceptor (pY)-phosphatase and mutation causes JMML. The structural hierarchy of SHP2 includes protein tyrosine phosphatase domain (PTP) and Src-homology 2 domain (N-SH2 and C-SH2). Somatic mutation (E76Q) in the interface of SH2-PTP domain is the most commonly identified mutation found in up to 35% of patients with JMML. The mechanism of this mutant associated with JMML is poorly understood. Here, molecular dynamics simulation was performed on wild-type and mutant (E76Q) of SHP2 to explore the precise impact of gain-of-function on PTP’s activity. Consequently, such impact rescues the SHP2 protein from autoinhibition state through losing the interface interactions of Q256/F7 and S502/Q76 or weakening interactions of Q256/R4, Q510/G60, and Q506/A72 between N-SH2 and PTP domains. The consequences of these interactions further relieve the D′E loop away from the PTP catalytic site. The following study would provide a mechanistic insight for better understanding of how individual SHP2 mutations alter the PTP’s activity at the atomic level.
Hepatitis C virus (HCV) is a notorious member of the enveloped, positive-strand RNA flavivirus family. Non-structural protein 5A (NS5A) plays a key role in HCV replication and assembly. NS5A is...
NLRP3-PYD inflammasome activates an inflammatory pathway in response to a wide variety of cell damage or infections. Dysregulated NLRP3 inflammatory signaling has many chronic inflammatory and autoimmune disorders. NLRP3 and ASC have a PYD, a superfamily member of the Death Domain, which plays a key role in inflammatory assembly. The ASC interacts with NLRP3 through a homotypic PYD and recruits the procaspase-1 through a homotypic caspase recruitment domain interaction. Here, we used several computational approaches to reveal the interactions of the NLRP3 and ASC PYD domains that lead to the activation of the inflammasome complex. We have characterized ASC and NLRP3-PYD intermolecular interactions by protein−protein docking, and further molecular dynamics (MD) simulations were conducted to evaluate the stability of NLRP3/ASC-PYD complex. Subsequently, we have identified several residues that stabilize the NLRP3/ASC-PYD complex in different faces (i.e., Face-1 to Face-4). The research framework offers new insights into the molecular mechanisms of inflammasome and apoptosis signaling as well as the ease of the drug discovery process.
Background: Resistance to the critical first line anti-tubercular drug, Pyrazinamide, is a significant obstacle to achieving the global end to tuberculosis targets. Approximately 50% of multidrug-resistant tuberculosis and over 90% of extensively drug-resistant tuberculosis strains are also Pyrazinamide resistant. Pyrazinamide is a pro-drug that reduce the duration of tuberculosis therapy time by 9-12 months, while used as an anti-biotic in the 1st- & 2nd-line tuberculosis treatment regimens. Pyrazinamidase is an enzyme, encoded by pncA gene, is responsible for the amide hydrolysis of Pyrazinamide into active Pyrazinoic acid. Pyrazinoic acid, could inhibit trans-translation by binding to Ribosomal protein S1 and competing with tmRNA, the natural cofactor of Ribosomal protein S1. Although pncA mutations have been commonly associated with Pyrazinamide resistance, a small number of resistance cases have been associated with mutations in Ribosomal protein S1. Ribosomal protein S1was recently identified as a possible target of Pyrazinamide based on its binding activity to Pyrazinoic acid and the capacity to inhibit trans-translation. Objective: Despite the critical role played by Pyrazinamide, its mechanisms of action are not yet fully understood. Therefore, an effort to explore the resistance mechanism toward Pyrazinamide drug in Mycobacterium (M.) tuberculosis. Methods: An extensive molecular dynamics simulation was performed using the AMBER software package. We mutated residues of the binding site (i.e., F307A, F310A, and R357A) in the RpsA S1 domain to address the drug-resistant mechanism of RpsA in complex that might be responsible for Pyrazinamide resistance. Moreover, it is challenging to collect the drug mutant combine complex of a protein by single-crystal X-ray diffraction. Thus, the total three structures were prepared by inducing mutations in the wild-type protein using PyMol. Results: The dynamics results revealed that mutation in binding pocket produced Pyrazinamide resistance due to the specificity of these residues in binding pockets which result in scarcity of hydrophobic and hydrogen bonding interaction with Pyrazinoic acid, which increases the CA-distance between the binding pocket residues as compared to wild type RpsA that lead to structural instability. Conclusion: The overall dynamic results will provide useful information behind the drug resistance mechanism to manage tuberculosis and also helps in better management for future drug resistance.
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