5O4K

Crystal structure of P450 CYP121 in complex with compound 6b.

5O4K の概要

• エントリーDOI: 10.2210/pdb5o4k/pdb
• 分子名称: Mycocyclosin synthase, SULFATE ION, PROTOPORPHYRIN IX CONTAINING FE, ... (5 entities in total)
• 機能のキーワード: cytochrome p450 redox inhibitor, oxidoreductase
• 由来する生物種: Mycobacterium tuberculosis CDC1551
• 細胞内の位置: Cytoplasm : P9WPP6
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44543.37

構造登録者

Levy, C.W. (登録日: 2017-05-29, 公開日: 2018-03-28, 最終更新日: 2024-01-17)

主引用文献

Taban, I.M.,Elshihawy, H.E.A.E.,Torun, B.,Zucchini, B.,Williamson, C.J.,Altuwairigi, D.,Ngu, A.S.T.,McLean, K.J.,Levy, C.W.,Sood, S.,Marino, L.B.,Munro, A.W.,de Carvalho, L.P.S.,Simons, C.
Novel Aryl Substituted Pyrazoles as Small Molecule Inhibitors of Cytochrome P450 CYP121A1: Synthesis and Antimycobacterial Evaluation.
J. Med. Chem., 60:10257-10267, 2017

PubMed Abstract: Three series of biarylpyrazole imidazole and triazoles are described, which vary in the linker between the biaryl pyrazole and imidazole/triazole group. The imidazole and triazole series with the short -CH- linker displayed promising antimycobacterial activity, with the imidazole-CH- series (7) showing low MIC values (6.25-25 μg/mL), which was also influenced by lipophilicity. Extending the linker to -C(O)NH(CH)- resulted in a loss of antimycobacterial activity. The binding affinity of the compounds with CYP121A1 was determined by UV-visible optical titrations with K values of 2.63, 35.6, and 290 μM, respectively, for the tightest binding compounds 7e, 8b, and 13d from their respective series. Both binding affinity assays and docking studies of the CYP121A1 inhibitors suggest type II indirect binding through interstitial water molecules, with key binding residues Thr77, Val78, Val82, Val83, Met86, Ser237, Gln385, and Arg386, comparable with the binding interactions observed with fluconazole and the natural substrate dicyclotyrosine.

PubMed: 29185746
DOI: 10.1021/acs.jmedchem.7b01562

実験手法

X-RAY DIFFRACTION (1.5 Å)