Summary for 7OBO
| Entry DOI | 10.2210/pdb7obo/pdb |
| Descriptor | Glutathione transferase, (2~{S})-2-azanyl-5-[[(2~{R})-1-(2-hydroxy-2-oxoethylamino)-3-[(7-nitro-2,1,3-benzoxadiazol-4-yl)sulfanyl]-1-oxidanylidene-propan-2-yl]amino]-5-oxidanylidene-pentanoic acid (3 entities in total) |
| Functional Keywords | glutathione-s-transferase, ligandin, flavonoid binding, mult-herbicide resistence, transferase |
| Biological source | Alopecurus myosuroides |
| Total number of polymer chains | 1 |
| Total formula weight | 25464.20 |
| Authors | Pohl, E.,Eno, R.F.M.,Freitag-Pohl, S. (deposition date: 2021-04-23, release date: 2022-04-20, Last modification date: 2024-01-31) |
| Primary citation | Schwarz, M.,Eno, R.F.M.,Freitag-Pohl, S.,Coxon, C.R.,Straker, H.E.,Wortley, D.J.,Hughes, D.J.,Mitchell, G.,Moore, J.,Cummins, I.,Onkokesung, N.,Brazier-Hicks, M.,Edwards, R.,Pohl, E.,Steel, P.G. Flavonoid-based inhibitors of the Phi-class glutathione transferase from black-grass to combat multiple herbicide resistance. Org.Biomol.Chem., 19:9211-9222, 2021 Cited by PubMed Abstract: The evolution and growth of multiple-herbicide resistance (MHR) in grass weeds continues to threaten global cereal production. While various processes can contribute to resistance, earlier work has identified the phi class glutathione--transferase (GSTF1) as a functional biomarker of MHR in black-grass (). This study provides further insights into the role of GSTF1 in MHR using a combination of chemical and structural biology. Crystal structures of wild-type GSTF1, together with two specifically designed variants that allowed the co-crystal structure determination with glutathione and a glutathione adduct of the GSTF1 inhibitor 4-chloro-7-nitro-benzofurazan (NBD-Cl) were obtained. These studies demonstrated that the inhibitory activity of NBD-Cl was associated with the occlusion of the active site and the impediment of substrate binding. A search for other selective inhibitors of GSTF1, using ligand-fishing experiments, identified a number of flavonoids as potential ligands. Subsequent experiments using black-grass extracts discovered a specific flavonoid as a natural ligand of the recombinant enzyme. A series of related synthetic flavonoids was prepared and their binding to GSTF1 was investigated showing a high affinity for derivatives bearing a -5-decyl-α-carboxylate. Molecular modelling based on high-resolution crystal structures allowed a binding pose to be defined which explained flavonoid binding specificity. Crucially, high binding affinity was linked to a reversal of the herbicide resistance phenotype in MHR black-grass. Collectively, these results present a nature-inspired new lead for the development of herbicide synergists to counteract MHR in weeds. PubMed: 34643629DOI: 10.1039/d1ob01802g PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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