8CCI

Crystal structure of Mycobacterium smegmatis thioredoxin reductase

Summary for 8CCI

• Entry DOI: 10.2210/pdb8cci/pdb
• Descriptor: Thioredoxin reductase, FLAVIN-ADENINE DINUCLEOTIDE, GLYCEROL, ... (6 entities in total)
• Functional Keywords: trxr, oxidoreductase
• Biological source: Mycolicibacterium smegmatis MC2 155
• Total number of polymer chains: 1
• Total formula weight: 35684.77

Authors

Fuesser, F.T.,Koch, O.,Kuemmel, D. (deposition date: 2023-01-27, release date: 2023-07-26, Last modification date: 2024-11-06)

Primary citation

Fusser, F.T.,Wollenhaupt, J.,Weiss, M.S.,Kummel, D.,Koch, O.
Novel starting points for fragment-based drug design against mycobacterial thioredoxin reductase identified using crystallographic fragment screening.
Acta Crystallogr D Struct Biol, 79:857-865, 2023

PubMed Abstract: The increasing number of people dying from tuberculosis and the existence of extensively drug-resistant strains has led to an urgent need for new antituberculotic drugs with alternative modes of action. As part of the thioredoxin system, thioredoxin reductase (TrxR) is essential for the survival of Mycobacterium tuberculosis (Mtb) and shows substantial differences from human TrxR, making it a promising and most likely selective target. As a model organism for Mtb, crystals of Mycobacterium smegmatis TrxR that diffracted to high resolution were used in crystallographic fragment screening to discover binding fragments and new binding sites. The application of the 96 structurally diverse fragments from the F2X-Entry Screen revealed 56 new starting points for fragment-based drug design of new TrxR inhibitors. Over 200 crystal structures were analyzed using FragMAXapp, which includes processing and refinement by largely automated software pipelines and hit identification via the multi-data-set analysis approach PanDDA. The fragments are bound to 11 binding sites, of which four are positioned at binding pockets or important interaction sites and therefore show high potential for possible inhibition of TrxR.

PubMed: 37574972
DOI: 10.1107/S2059798323005223

Experimental method

X-RAY DIFFRACTION (1.56 Å)