2XC3

X-ray structure of Mycobacterium tuberculosis cyp125 bound to the reverse type I inhibitor

Summary for 2XC3

• Entry DOI: 10.2210/pdb2xc3/pdb
• Related: 2X5L 2X5W
• Descriptor: PUTATIVE CYTOCHROME P450 125, PROTOPORPHYRIN IX CONTAINING FE, NALPHA-[(TRANS-4-METHYLCYCLOHEXYL)CARBONYL]-N-PYRIDIN-4-YL-D-TRYPTOPHANAMIDE, ... (4 entities in total)
• Functional Keywords: oxidoreductase, metal-binding
• Biological source: MYCOBACTERIUM TUBERCULOSIS
• Total number of polymer chains: 1
• Total formula weight: 48614.50

Authors

Ouellet, H.,Kells, P.M.,Ortiz de Montellano, P.R.,Podust, L.M. (deposition date: 2010-04-16, release date: 2010-11-10, Last modification date: 2023-12-20)

Primary citation

Ouellet, H.,Kells, P.M.,Ortiz de Montellano, P.R.,Podust, L.M.
Reverse Type I Inhibitor of Mycobacteriumtuberculosis Cyp125A1.
Bioorg.Med.Chem.Lett., 21:332-, 2011

PubMed Abstract: Cytochrome P450 CYP125A1 of Mycobacterium tuberculosis, a potential therapeutic target for tuberculosis in humans, initiates degradation of the aliphatic chain of host cholesterol and is essential for establishing M. tuberculosis infection in a mouse model of disease. We explored the interactions of CYP125A1 with a reverse type I inhibitor by X-ray structure analysis and UV-vis spectroscopy. Compound LP10 (α-[(4-methylcyclohexyl)carbonyl amino]-N-4-pyridinyl-1H-indole-3-propanamide), previously identified as a potent type II inhibitor of Trypanosomacruzi CYP51, shifts CYP125A1 to a water-coordinated low-spin state upon binding with low micromolar affinity. When LP10 is present in the active site, the crystal structure and spectral characteristics both demonstrate changes in lipophilic and electronic properties favoring coordination of the iron axial water ligand. These results provide an insight into the structural requirements for developing selective CYP125A1 inhibitors.

PubMed: 21109436
DOI: 10.1016/J.BMCL.2010.11.007

Experimental method

X-RAY DIFFRACTION (1.5 Å)