7QNN
Crystal structure of CYP125 from Mycobacterium tuberculosis in complex with inhibitor (surface entropy reduction mutant)
Summary for 7QNN
| Entry DOI | 10.2210/pdb7qnn/pdb |
| Descriptor | Steroid C26-monooxygenase, PROTOPORPHYRIN IX CONTAINING FE, ethyl 1-(cyclopentylmethyl)-5-pyridin-4-yl-indole-2-carboxylate, ... (4 entities in total) |
| Functional Keywords | p450, cyp, tuberculosis, cholesterol, inhibitor, complex, surface, entropy, reduction, cytochrome, oxidoreductase |
| Biological source | Mycobacterium tuberculosis |
| Total number of polymer chains | 1 |
| Total formula weight | 47454.00 |
| Authors | Snee, M.,Tunnicliffe, R.,Leys, D.,Levy, C.,Katariya, M. (deposition date: 2021-12-21, release date: 2022-12-28, Last modification date: 2024-02-07) |
| Primary citation | Katariya, M.M.,Snee, M.,Tunnicliffe, R.B.,Kavanagh, M.E.,Boshoff, H.I.M.,Amadi, C.N.,Levy, C.W.,Munro, A.W.,Abell, C.,Leys, D.,Coyne, A.G.,McLean, K.J. Structure Based Discovery of Inhibitors of CYP125 and CYP142 from Mycobacterium tuberculosis. Chemistry, 29:e202203868-e202203868, 2023 Cited by PubMed Abstract: Mycobacterium tuberculosis (Mtb) was responsible for approximately 1.6 million deaths in 2021. With the emergence of extensive drug resistance, novel therapeutic agents are urgently needed, and continued drug discovery efforts required. Host-derived lipids such as cholesterol not only support Mtb growth, but are also suspected to function in immunomodulation, with links to persistence and immune evasion. Mtb cytochrome P450 (CYP) enzymes facilitate key steps in lipid catabolism and thus present potential targets for inhibition. Here we present a series of compounds based on an ethyl 5-(pyridin-4-yl)-1H-indole-2-carboxylate pharmacophore which bind strongly to both Mtb cholesterol oxidases CYP125 and CYP142. Using a structure-guided approach, combined with biophysical characterization, compounds with micromolar range in-cell activity against clinically relevant drug-resistant isolates were obtained. These will incite further development of much-needed additional treatment options and provide routes to probe the role of CYP125 and CYP142 in Mtb pathogenesis. PubMed: 36912255DOI: 10.1002/chem.202203868 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.47 Å) |
Structure validation
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