6T0J
Crystal structure of CYP124 in complex with SQ109
Summary for 6T0J
| Entry DOI | 10.2210/pdb6t0j/pdb |
| Descriptor | Methyl-branched lipid omega-hydroxylase, PROTOPORPHYRIN IX CONTAINING FE, N-[(2Z)-3,7-dimethylocta-2,6-dien-1-yl]-N'-[(1R,3S,5R,7R)-tricyclo[3.3.1.1~3,7~]dec-2-yl]ethane-1,2-diamine, ... (8 entities in total) |
| Functional Keywords | cytochrome, p450, cyp, oxidoreductase, sq109, sq, 109, mmpl3, tuberculosis, mycobacterium tuberculosis, antituberculosis, drug, substrate |
| Biological source | Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) |
| Total number of polymer chains | 1 |
| Total formula weight | 50509.20 |
| Authors | Bukhdruker, S.,Marin, E.,Varaksa, T.,Gilep, A.,Strushkevich, N.,Borshchevskiy, V. (deposition date: 2019-10-03, release date: 2020-10-14, Last modification date: 2024-01-24) |
| Primary citation | Bukhdruker, S.,Varaksa, T.,Grabovec, I.,Marin, E.,Shabunya, P.,Kadukova, M.,Grudinin, S.,Kavaleuski, A.,Gusach, A.,Gilep, A.,Borshchevskiy, V.,Strushkevich, N. Hydroxylation of Antitubercular Drug Candidate, SQ109, by Mycobacterial Cytochrome P450. Int J Mol Sci, 21:-, 2020 Cited by PubMed Abstract: Spreading of the multidrug-resistant (MDR) strains of the one of the most harmful pathogen (Mtb) generates the need for new effective drugs. SQ109 showed activity against resistant Mtb and already advanced to Phase II/III clinical trials. Fast SQ109 degradation is attributed to the human liver Cytochrome P450s (CYPs). However, no information is available about interactions of the drug with Mtb CYPs. Here, we show that Mtb CYP124, previously assigned as a methyl-branched lipid monooxygenase, binds and hydroxylates SQ109 in vitro. A 1.25 Å-resolution crystal structure of the CYP124-SQ109 complex unambiguously shows two conformations of the drug, both positioned for hydroxylation of the ω-methyl group in the trans position. The hydroxylated SQ109 presumably forms stabilizing H-bonds with its target, Mycobacterial membrane protein Large 3 (MmpL3). We anticipate that Mtb CYPs could function as analogs of drug-metabolizing human CYPs affecting pharmacokinetics and pharmacodynamics of antitubercular (anti-TB) drugs. PubMed: 33081390DOI: 10.3390/ijms21207683 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.25 Å) |
Structure validation
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