8DWR

Crystal structure of the L333V variant of catalase-peroxidase from Mycobacterium tuberculosis

Summary for 8DWR

• Entry DOI: 10.2210/pdb8dwr/pdb
• Related: 1SJ2 2CCA
• Descriptor: Catalase-peroxidase, PROTOPORPHYRIN IX CONTAINING FE, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (6 entities in total)
• Functional Keywords: catalase-peroxidase, katg, oxidoreductase, heme
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 4
• Total formula weight: 330249.73

Authors

Diaz-Vilchis, A.,Uribe-Vazquez, B.,Avila-Linares, A.,Rudino-Pinera, E.,Soberon, X. (deposition date: 2022-08-01, release date: 2023-08-02, Last modification date: 2024-03-13)

Primary citation

Uribe-Vazquez, B.,Diaz-Vilchis, A.,Avila-Linares, A.,Saab-Rincon, G.,Marin-Tovar, Y.,Flores, H.,Pastor, N.,Huerta-Miranda, G.,Rudino-Pinera, E.,Soberon, X.
Characterization of a catalase-peroxidase variant (L333V-KatG) identified in an INH-resistant Mycobacterium tuberculosis clinical isolate.
Biochem Biophys Rep, 37:101649-101649, 2024

PubMed Abstract: catalase-peroxidase (-KatG) is a bifunctional heme-dependent enzyme that has been shown to activate isoniazid (INH), the widely used antibiotic against tuberculosis (TB). The L333V-KatG variant has been associated with INH resistance in clinical isolates from Mexico. To understand better the mechanisms of INH activation, its catalytic properties (catalase, peroxidase, and IN-NAD formation) and crystal structure were compared with those of the wild-type enzyme (WT-KatG). The rate of IN-NAD formation mediated by WT-KatG was 23% greater than L333V-KatG when INH concentration is varied. In contrast to WT-KatG, the crystal structure of the L333V-KatG variant has a perhydroxy modification of the indole nitrogen of W107 from MYW adduct. L333V-KatG shows most of the active site residues in a similar position to WT-KatG; only R418 is in the R-conformation instead of the double R and Y conformation present in WT-KatG. L333V-KatG shows a small displacement respect to WT-KatG in the helix from R385 to L404 towards the mutation site, an increase in length of the coordination bond between H270 and heme Fe, and a longer H-bond between proximal D381 and W321, compared to WT-KatG; these small displacements could explain the altered redox potential of the heme, and result in a less active and stable enzyme.

PubMed: 38318524
DOI: 10.1016/j.bbrep.2024.101649

Experimental method

X-RAY DIFFRACTION (2.1 Å)