Prediction of naturally occurring plant based compounds as anticancer agents is the key to developing new chemical entities in the area of therapeutic oncology. A webserver for assessing anticancer potential of phytomolecules has been developed.
Among the two GroEL paralogs in Mycobacterium tuberculosis, GroEL1 and GroEL2, GroEL1 has a characteristic histidine-rich C terminus. Since histidine richness is likely to be involved in metal binding, we attempted to decipher the role of GroEL1 in chelating metals and the consequence on M. tuberculosis physiology. Isothermal titration calorimetry showed that GroEL1 binds copper and other metals. Mycobacterial viability assay, redox balance, and DNA protection assay concluded that GroEL1 protects from copper stress in vitro. Solution X-ray scattering and constrained modeling of GroEL1 À/+ copper ions showed reorientation of the apical domain as seen in functional assembly. We conclude that the duplication of chaperonin genes in M. tuberculosis might have led to their evolutionary divergence and consequent functional divergence of chaperonins.
The artemisinin‐resistant mutations in Plasmodium falciparum (PfKelch13) identified worldwide are mostly confined to the Broad‐complex, tramtrack and bric‐à‐brac/poxvirus and zinc‐finger (BTB/POZ) and Kelch‐repeat propeller (KRP) domains. To date, only two crystal structures of the BTB/POZ‐KRP domains as tight dimers are available, which limits structure‐based predictions and interpretation of its role(s) in inducing clinical artemisinin resistance. Our solution Small‐Angle X‐ray Scattering (SAXS) data analysis and shape restoration brought forth that: (a) PfKelch13 forms a stable hexamer in P6 symmetry, (b) interactions of the N‐termini drive the hexameric assembly, and (c) the six KRP domains project independently in space, forming a cauldron‐like architecture. We further deduce that the artemisinin‐sensitive mutant A578S is packed like the wild‐type protein, however, hexameric assemblies of the predominant artemisinin‐resistant mutants R539T and C580Y displayed detectable differences in the spatial positioning of their BTB/POZ‐KRP domains. Lastly, mapping of mutations known to enable artemisinin resistance suggested evolutionary pressure in the selection for mutations in the BTB/POZ‐KRP domains. These mutations appear non‐detrimental to the hexameric assembly of proteins, and yet somehow alter the flux of downstream events essential for the susceptibility to artemisinin.
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