6BPY

Aspergillus fumigatus Thioredoxin Reductase

Summary for 6BPY

• Entry DOI: 10.2210/pdb6bpy/pdb
• Descriptor: Thioredoxin reductase, FLAVIN-ADENINE DINUCLEOTIDE, MALONATE ION, ... (8 entities in total)
• Functional Keywords: redox homeostasis, rossmann fold, dithiol, oxidoreductase
• Biological source: Neosartorya fumigata (Aspergillus fumigatus)
• Total number of polymer chains: 2
• Total formula weight: 83921.58

Authors

Marshall, A.C.,Bruning, J.B. (deposition date: 2017-11-27, release date: 2019-01-09, Last modification date: 2024-10-30)

Primary citation

Marshall, A.C.,Kidd, S.E.,Lamont-Friedrich, S.J.,Arentz, G.,Hoffmann, P.,Coad, B.R.,Bruning, J.B.
Structure, Mechanism, and Inhibition ofAspergillus fumigatusThioredoxin Reductase.
Antimicrob.Agents Chemother., 63:-, 2019

PubMed Abstract: infections are associated with high mortality rates and high treatment costs. Limited available antifungals and increasing antifungal resistance highlight an urgent need for new antifungals. Thioredoxin reductase (TrxR) is essential for maintaining redox homeostasis and presents as a promising target for novel antifungals. We show that ebselen [2-phenyl-1,2-benzoselenazol-3(2H)-one] is an inhibitor of TrxR ( = 0.22 μM) and inhibits growth of spp., with MIC values of 16 to 64 µg/ml. Mass spectrometry analysis demonstrates that ebselen interacts covalently with a catalytic cysteine of TrxR, Cys148. We also present the X-ray crystal structure of TrxR and use modeling of the enzyme-inhibitor complex to outline key molecular interactions. This provides a scaffold for future design of potent and selective antifungal drugs that target TrxR, improving the potency of ebselen toward inhbition of growth.

PubMed: 30642940
DOI: 10.1128/AAC.02281-18

Experimental method

X-RAY DIFFRACTION (3.201 Å)