Description
Experimental Technique/Method:X-RAY DIFFRACTION
Resolution:1.75
Classification:TRANSFERASE
Release Date:2013-12-18
Deposition Date:2013-09-21
Revision Date:2014-01-15
Molecular Weight:30683.1
Macromolecule Type:Protein
Residue Count:259
Atom Site Count:2147
DOI:10.2210/pdb4mub/pdb
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.
Resolution:1.75
Classification:TRANSFERASE
Release Date:2013-12-18
Deposition Date:2013-09-21
Revision Date:2014-01-15
Molecular Weight:30683.1
Macromolecule Type:Protein
Residue Count:259
Atom Site Count:2147
DOI:10.2210/pdb4mub/pdb
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.
| Date made available | 2013 |
|---|---|
| Publisher | RCSB-PDB |