4MUA

Schistosoma mansoni (Blood Fluke) Sulfotransferase

Summary for 4MUA

• Entry DOI: 10.2210/pdb4mua/pdb
• Descriptor: Sulfotransferase, ADENOSINE-3'-5'-DIPHOSPHATE, SODIUM ION, ... (4 entities in total)
• Functional Keywords: pap, parasite, helminth, drug resistance, transferase
• Biological source: Schistosoma mansoni (Blood fluke)
• Total number of polymer chains: 1
• Total formula weight: 30426.75

Authors

Valentim, C.L.L.,Cioli, D.,Chevalier, F.D.,Cao, X.,Taylor, A.B.,Holloway, S.P.,Pica-Mattoccia, L.,Guidi, A.,Basso, A.,Tsai, I.J.,Berriman, M.,Carvalho-Queiroz, C.,Almeida, M.,Aguilar, H.,Frantz, D.E.,Hart, P.J.,Anderson, T.J.C.,LoVerde, P.T. (deposition date: 2013-09-21, release date: 2013-12-18, Last modification date: 2024-02-28)

Primary citation

Valentim, C.L.,Cioli, D.,Chevalier, F.D.,Cao, X.,Taylor, A.B.,Holloway, S.P.,Pica-Mattoccia, L.,Guidi, A.,Basso, A.,Tsai, I.J.,Berriman, M.,Carvalho-Queiroz, C.,Almeida, M.,Aguilar, H.,Frantz, D.E.,Hart, P.J.,LoVerde, P.T.,Anderson, T.J.
Genetic and molecular basis of drug resistance and species-specific drug action in schistosome parasites.
Science, 342:1385-1389, 2013

PubMed Abstract: Oxamniquine resistance evolved in the human blood fluke (Schistosoma mansoni) in Brazil in the 1970s. We crossed parental parasites differing ~500-fold in drug response, determined drug sensitivity and marker segregation in clonally derived second-generation progeny, and identified a single quantitative trait locus (logarithm of odds = 31) on chromosome 6. A sulfotransferase was identified as the causative gene by using RNA interference knockdown and biochemical complementation assays, and we subsequently demonstrated independent origins of loss-of-function mutations in field-derived and laboratory-selected resistant parasites. These results demonstrate the utility of linkage mapping in a human helminth parasite, while crystallographic analyses of protein-drug interactions illuminate the mode of drug action and provide a framework for rational design of oxamniquine derivatives that kill both S. mansoni and S. haematobium, the two species responsible for >99% of schistosomiasis cases worldwide.

PubMed: 24263136
DOI: 10.1126/science.1243106

Experimental method

X-RAY DIFFRACTION (1.95 Å)