7NPX

Thioredoxin glutathione reductase from Schistosoma mansoni in complex with 3-(3-Methoxyquinoxalin-2-yl)propanoic acid at 24 hours of soaking

Summary for 7NPX

• Entry DOI: 10.2210/pdb7npx/pdb
• Descriptor: Thioredoxin glutathione reductase, FLAVIN-ADENINE DINUCLEOTIDE, 3-(3-methoxyquinoxalin-2-yl)propanoic acid, ... (7 entities in total)
• Functional Keywords: fragment binding, redox enzyme, inhibitor, flavoreductase, protein binding
• Biological source: Schistosoma mansoni (Blood fluke)
• Total number of polymer chains: 2
• Total formula weight: 132974.34

Authors

Fata, F.,Silvestri, I.,Williams, D.L.,Angelucci, F. (deposition date: 2021-02-28, release date: 2021-05-19, Last modification date: 2024-11-13)

Primary citation

Fata, F.,Silvestri, I.,Ardini, M.,Ippoliti, R.,Di Leandro, L.,Demitri, N.,Polentarutti, M.,Di Matteo, A.,Lyu, H.,Thatcher, G.R.J.,Petukhov, P.A.,Williams, D.L.,Angelucci, F.
Probing the Surface of a Parasite Drug Target Thioredoxin Glutathione Reductase Using Small Molecule Fragments.
Acs Infect Dis., 7:1932-1944, 2021

PubMed Abstract: Fragment screening is a powerful drug discovery approach particularly useful for enzymes difficult to inhibit selectively, such as the thiol/selenol-dependent thioredoxin reductases (TrxRs), which are essential and druggable in several infectious diseases. Several known inhibitors are reactive electrophiles targeting the selenocysteine-containing C-terminus and thus often suffering from off-target reactivity . The lack of structural information on the interaction modalities of the C-terminus-targeting inhibitors, due to the high mobility of this domain and the lack of alternative druggable sites, prevents the development of selective inhibitors for TrxRs. In this work, fragments selected from actives identified in a large screen carried out against Thioredoxin Glutathione Reductase from (SmTGR) were probed by X-ray crystallography. SmTGR is one of the most promising drug targets for schistosomiasis, a devastating, neglected disease. Utilizing a multicrystal method to analyze electron density maps, structural analysis, and functional studies, three binding sites were characterized in SmTGR: two sites are close to or partially superposable with the NADPH binding site, while the third one is found between two symmetry related SmTGR subunits of the crystal lattice. Surprisingly, one compound bound to this latter site stabilizes, through allosteric effects mediated by the so-called guiding bar residues, the crucial redox active C-terminus of SmTGR, making it finally visible at high resolution. These results further promote fragments as small molecule probes for investigating functional aspects of the target protein, exemplified by the allosteric effect on the C-terminus, and providing fundamental chemical information exploitable in drug discovery.

PubMed: 33950676
DOI: 10.1021/acsinfecdis.0c00909

Experimental method

X-RAY DIFFRACTION (2.7 Å)