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• W4225073124 endingPage "4962" @default.
• W4225073124 startingPage "4935" @default.
• W4225073124 abstract "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." @default.
• W4225073124 created "2022-04-29" @default.
• W4225073124 creator A5006010717 @default.
• W4225073124 creator A5011301492 @default.
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• W4225073124 creator A5037432950 @default.
• W4225073124 creator A5054541671 @default.
• W4225073124 creator A5081288778 @default.
• W4225073124 date "2022-02-10" @default.
• W4225073124 modified "2023-10-12" @default.
• W4225073124 title "<i>Plasmodium falciparum</i> Kelch13 and its artemisinin‐resistant mutants assemble as hexamers in solution: a SAXS data‐driven modelling study" @default.
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• W4225073124 doi "https://doi.org/10.1111/febs.16378" @default.
• W4225073124 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/35092154" @default.
• W4225073124 hasPublicationYear "2022" @default.
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