dc.contributor.author | Huhn, Jason | |
dc.contributor.author | Jeffrey, Philip D. | |
dc.contributor.author | Larsen, Kristofer | |
dc.contributor.author | Rundberget, Thomas | |
dc.contributor.author | Rise, Frode | |
dc.contributor.author | Cox, Neil R. | |
dc.contributor.author | Arcus, Vickery L. | |
dc.contributor.author | Shi, Yigong | |
dc.contributor.author | Miles, Christopher O. | |
dc.coverage.spatial | United States | en_NZ |
dc.date.accessioned | 2009-12-03T02:07:27Z | |
dc.date.available | 2009-12-03T02:07:27Z | |
dc.date.issued | 2009 | |
dc.identifier.citation | Huhn, J., Jeffrey, P. D., Larsen, K., Rundberget, T., Rise, F., Cox, N. R., Arcus, V., Shi, Y. & Miles, C. O. (2009). A Structural Basis for the reduced toxicity of dinophysistoxin-2. Chemical Research in Toxicology, 22(11), 1782-1786. | en |
dc.identifier.uri | https://hdl.handle.net/10289/3456 | |
dc.description.abstract | Okadaic acid (OA), dinophysistoxin-1 (DTX-1), and dinophysistoxin-2 (DTX-2) are algal toxins that can accumulate in shellfish and cause diarrhetic shellfish poisoning. Recent studies indicate that DTX-2 is about half as toxic and has about half the affinity for protein phosphatase 2A (PP2A) as OA. NMR structural studies showed that DTX-1 possessed an equatorial 35-methyl group but that DTX-2 had an axial 35-methyl group. Molecular modeling studies indicated that an axial 35-methyl could exhibit unfavorable interactions in the PP2A binding site, and this has been proposed as the reason for the reduced toxicity of DTX-2. Statistical analyses of published data indicate that the affinity of PP2A for DTX-1 is 1.6-fold higher, and for DTX-2 is 2-fold lower, than for OA. We obtained X-ray crystal structures of DTX-1 and DTX-2 bound to PP2A. The crystal structures independently confirm the C-35 stereochemistries determined in the earlier NMR study. The structure for the DTX-1 complex was virtually identical to that of the OA-PP2A complex, except for the presence of the equatorial 35-methyl on the ligand. The favorable placement of the equatorial 35-methyl group of DTX-1 against the aromatic π-bonds of His191 may account for the increased affinity of PP2A toward DTX-1. In contrast, the axial 35-methyl of DTX-2 caused the side chain of His191 to rotate 140° so that it pointed toward the solvent, thereby opening one end of the hydrophobic binding cage. This rearrangement to accommodate the unfavorable interaction from the axial 35-methyl of DTX-2 reduces the binding energy and appears to be responsible for the reduced affinity of PP2A for DTX-2. These results highlight the potential of molecular modeling studies for understanding the relative toxicity of analogues once the binding site at the molecular target has been properly characterized. | en |
dc.language.iso | en | |
dc.publisher | American Chemical Society | en_NZ |
dc.relation.uri | http://pubs.acs.org/doi/pdf/10.1021/tx9001622 | en |
dc.subject | dinophysistoxin | en |
dc.subject | multiple reaction monitoring | en |
dc.subject | protein phosphatise | en |
dc.subject | okadaic acid | en |
dc.subject | toxic equivalence factor | en |
dc.title | A structural basis for the reduced toxicity of dinophysistoxin-2 | en |
dc.type | Journal Article | en |
dc.identifier.doi | 10.1021/tx9001622 | en |
dc.relation.isPartOf | Chemical Research in Toxicology | en_NZ |
pubs.begin-page | 1782 | en_NZ |
pubs.elements-id | 34526 | |
pubs.end-page | 1786 | en_NZ |
pubs.issue | 11 | en_NZ |
pubs.volume | 22 | en_NZ |