8S4M
Crystal structure of Mycobacterium tuberculosis cytochrome P450 CYP125 in complex with an inhibitor
This is a non-PDB format compatible entry.
Summary for 8S4M
| Entry DOI | 10.2210/pdb8s4m/pdb |
| Related | 7ZGL 7ZIC |
| Descriptor | Steroid C26-monooxygenase, PROTOPORPHYRIN IX CONTAINING FE, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | cyp125, tuberculosis, cholesterol, p450, cyp, cytochrome, fragment, cholestenone, oxidoreductase |
| Biological source | Mycobacterium tuberculosis H37Rv |
| Total number of polymer chains | 3 |
| Total formula weight | 143142.63 |
| Authors | Snee, M.,Kavanagh, M.,Levy, C. (deposition date: 2024-02-21, release date: 2025-01-29, Last modification date: 2025-08-06) |
| Primary citation | Kavanagh, M.E.,McLean, K.J.,Gilbert, S.H.,Amadi, C.N.,Snee, M.,Tunnicliffe, R.B.,Arora, K.,Boshoff, H.I.M.,Fanourakis, A.,Rebollo-Lopez, M.J.,Ortega, F.,Levy, C.W.,Munro, A.W.,Leys, D.,Abell, C.,Coyne, A.G. Fragment-Based Development of Small Molecule Inhibitors Targeting Mycobacterium tuberculosis Cholesterol Metabolism. J.Med.Chem., 68:14416-14441, 2025 Cited by PubMed Abstract: Tuberculosis is the deadliest infectious disease in history and new drugs are urgently required to combat multidrug-resistant (MDR) strains of (). Here, we exploit the relience of on host-derived cholesterol to develop a novel class of antitubercular compounds that target CYP125 and CYP142; the enzymes that catalyze the first step of cholesterol metabolism. A combination of fragment screening and structure-based drug design was used to identify a hit compound and guide synthetic optimization of a dual CYP125/142 ligand ( 40-160 nM), which potently inhibits enzyme activity in vitro ( < 100 nM), and the growth of in extracellular (MIC 0.4-1.5 μM) and intracellular assays (IC 1.7 μM). The structural data and lead compounds reported here will help study cholesterol metabolism and guide the development of novel antibiotics to combat MDR PubMed: 40653654DOI: 10.1021/acs.jmedchem.5c00478 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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