8A1R

cryo-EM structure of thioredoxin glutathione reductase in complex with a non-competitive inhibitor

Summary for 8A1R

• Entry DOI: 10.2210/pdb8a1r/pdb
• EMDB information: 15084
• Descriptor: Thioredoxin glutathione reductase, FLAVIN-ADENINE DINUCLEOTIDE, (2~{R},3~{R},4~{S},5~{R})-2-[3-[[[(1~{R},2~{R},3~{R},5~{S})-2,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl]amino]methyl]indol-1-yl]oxane-3,4,5-triol (3 entities in total)
• Functional Keywords: inhibitor, complex, flavoreductase, flavoprotein
• Biological source: Schistosoma mansoni
• Total number of polymer chains: 2
• Total formula weight: 132522.47

Authors

Ardini, M.,Angelucci, F.,Fata, F.,Gabriele, F.,Effantin, G.,Ling, W.,Williams, D.L.,Petukhova, V.Z.,Petukhov, P.A. (deposition date: 2022-06-01, release date: 2023-06-14, Last modification date: 2024-11-13)

Primary citation

Petukhova, V.Z.,Aboagye, S.Y.,Ardini, M.,Lullo, R.P.,Fata, F.,Byrne, M.E.,Gabriele, F.,Martin, L.M.,Harding, L.N.M.,Gone, V.,Dangi, B.,Lantvit, D.D.,Nikolic, D.,Ippoliti, R.,Effantin, G.,Ling, W.L.,Johnson, J.J.,Thatcher, G.R.J.,Angelucci, F.,Williams, D.L.,Petukhov, P.A.
Non-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo.
Nat Commun, 14:3737-3737, 2023

PubMed Abstract: Only praziquantel is available for treating schistosomiasis, a disease affecting more than 200 million people. Praziquantel-resistant worms have been selected for in the lab and low cure rates from mass drug administration programs suggest that resistance is evolving in the field. Thioredoxin glutathione reductase (TGR) is essential for schistosome survival and a validated drug target. TGR inhibitors identified to date are irreversible and/or covalent inhibitors with unacceptable off-target effects. In this work, we identify noncovalent TGR inhibitors with efficacy against schistosome infections in mice, meeting the criteria for lead progression indicated by WHO. Comparisons with previous in vivo studies with praziquantel suggests that these inhibitors outperform the drug of choice for schistosomiasis against juvenile worms.

PubMed: 37349300
DOI: 10.1038/s41467-023-39444-y

Experimental method

ELECTRON MICROSCOPY (3.6 Å)