Biology subjects

Keshri, V.

Publications and source records attributed to Keshri, V..

2 recordsLinked to original sources

bioRxiv2020

Structural dynamics of non-synonymous SNPs of histone methyltransferase EZH2 involved in Weaver Syndrome

Enhancer of zeste homolog 2 (EZH2) is a histone H3 lysine 27 methyltransferases. Non-synonymous SNPs (nsSNPs) in the ezh2 gene may cause Weaver Syndrome that is a prominent and rare congenital disorder. Several EZH2 genetic variants have been characterized and reported, but there is no information available on their structural dynamics. Our study employs an in silico approach for structural and functional characterization of EZH2 nsSNPs. We identified 19 EZH2 nsSNPs majorly associated with Weaver Syndrome, among which four SET-domain nsSNPs including V621M, A677T, R679C, and H689Y significantly affected EZH2 structure. We conducted the triplicate of 100 ns of molecular dynamics simulations (MDS) to compare the dynamic interaction behaviors between wild-type and mutants of EZH2 with their substrate, H3K27me0 peptide. The simulation results revealed that the mutants had higher levels of structural variations as evidenced by secondary structure, density, distance plots, and principal component analysis. Compared to EZH2-WT, the mutants A677T and H689Y have shown lower binding energy with H3K27me0 peptide due to the denaturing of 310 helixes as exemplified by MM/PBSA calculations and secondary structure analysis. Our analysis shed light on mechanisms of structural variations of EZH2 nsSNPs and lay a stone to develop mutant-based therapeutic strategies for the design of target-specific scaffolds against Weaver Syndrome.

molecular biology↗

bioRxiv2019

Paradoxical β-lactamase activity of archaeal encoding enzymes

{beta}-lactams targeting the bacterial cell wall are not active on archaea. Here, we figure out that annotation of genes as {beta}-lactamase in Archeae on the basis of homologous genes, initially annotated {beta}-lactamases, is a remnant of the identification of the original activities of this group of enzymes, which in fact, have multiple functions including nuclease, ribonuclease, {beta}-lactamase, or glyoxalase; which may specialized over time. We expressed a class B {beta}-lactamase enzyme from Methanosarcina barkeri that digest penicillin G. Moreover, while a weak glyoxalase activity was detected, a significant ribonuclease activity on bacterial and synthetic RNAs was demonstrated. The {beta}-lactamase activity was inhibited by a {beta}-lactamase inhibitor (sulbactam), but its RNAse activity was not. This gene appears to has been transferred to the Flavobacteriaceae group including Elizabethkingia genus in which the expressed gene shows a more specialized activity toward resistance to tienanmicin but no glyoxalase activity. The expressed class C-like {beta}-lactamase gene, also from Methanosarcina sp., shows also hydrolysis activity and was more closely related to DD-peptidase enzymes than known bacterial class C {beta}-lactamases. Our findings highlight the requalification needness of annotated enzymes as {beta}-lactamases and the specification overtime of multipotent enzymes in different ways in Archaea and bacteria.

microbiology↗