7QJL

Crystal structure of CYP142 from Mycobacterium tuberculosis in complex with an inhibitor

Summary for 7QJL

• Entry DOI: 10.2210/pdb7qjl/pdb
• Related: 7QWN
• Descriptor: Steroid C26-monooxygenase, PROTOPORPHYRIN IX CONTAINING FE, ACETATE ION, ... (6 entities in total)
• Functional Keywords: cyp, p450, complex, inhibitor, tb, tuberculosis, cholesterol, cytochrome, heme, oxidoreductase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 45632.68

Authors

Snee, M.,Levy, C.,Katariya, M. (deposition date: 2021-12-16, 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

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: 36912255
DOI: 10.1002/chem.202203868

Experimental method

X-RAY DIFFRACTION (1.38 Å)