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 | |
| Primary citation | Kavanagh, M.E.,McLean, K.J.,Gilbert, S.H.,Amadi, C.,Snee, M.,Tunnicliffe, R.B.,Arora, K.,Boshoff, H.I.,Fanourakis, A.,Rebello-Lopez, M.J.,Ortega-Muro, 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. Biorxiv, 2024 Cited by PubMed Abstract: () is the world's most deadly infectious pathogen and new drugs are urgently required to combat the emergence of multi- (MDR) and extensively- (XDR) drug resistant strains. The bacterium specifically upregulates sterol uptake pathways in infected macrophages and the metabolism of host-derived cholesterol is essential for long-term survival Here, we report the development of antitubercular small molecules that inhibit the cholesterol oxidases CYP125 and CYP142, which catalyze the initial step of cholesterol metabolism. An efficient biophysical fragment screen was used to characterize the structure-activity relationships of CYP125 and CYP142, and identify a non-azole small molecule that can bind to the heme cofactor of both enzymes. A structure-guided fragment-linking strategy was used to optimize the binding affinity of , yielding a potent dual CYP125/142 inhibitor (K CYP125/CYP142 = 0.04/0.16 μM). Compound potently inhibits the catalytic activity of CYP125 and CYP142 (K values < 0.1 μM), and rapidly depletes intracellular ATP (IC = 0.15 μM). The compound has antimicrobial activity against both drug susceptible and MDR MIC values 0.4 - 1.5 μM in extracellular assays, and inhibits the growth of in human macrophages (MIC = 1.7 μM) with good selectivity over mammalian cytotoxicity (LD ≥ 50 μM). The combination of small molecule inhibitors and structural data reported here provide useful tools to study the role of cholesterol metabolism in and are a promising step towards novel antibiotics targeting bioenergetic pathways, which could be used to help combat MDR-TB. PubMed: 39803573DOI: 10.1101/2024.10.28.620643 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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