7RTQ
Sterol 14alpha demethylase (CYP51) from Naegleria fowleri in complex with an inhibitor R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide
Summary for 7RTQ
| Entry DOI | 10.2210/pdb7rtq/pdb |
| Descriptor | Protein CYP51, PROTOPORPHYRIN IX CONTAINING FE, N-[(1R)-2-(1H-imidazol-1-yl)-1-(3,4',5-trifluoro[1,1'-biphenyl]-4-yl)ethyl]-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide, ... (4 entities in total) |
| Functional Keywords | cytochrome p450, cyp51, sterol 14 alpha- demethylase, oxidoreductase |
| Biological source | Naegleria fowleri (Brain eating amoeba) |
| Total number of polymer chains | 4 |
| Total formula weight | 218968.10 |
| Authors | Lepesheva, G.I.,Hargrove, T.Y.,Wawrzak, Z. (deposition date: 2021-08-13, release date: 2021-11-24, Last modification date: 2023-10-18) |
| Primary citation | Hargrove, T.Y.,Wawrzak, Z.,Rachakonda, G.,Nes, W.D.,Villalta, F.,Guengerich, F.P.,Lepesheva, G.I. Relaxed Substrate Requirements of Sterol 14 alpha-Demethylase from Naegleria fowleri Are Accompanied by Resistance to Inhibition. J.Med.Chem., 64:17511-17522, 2021 Cited by PubMed Abstract: is the protozoan pathogen that causes primary amoebic meningoencephalitis (PAM), with the death rate exceeding 97%. The amoeba makes sterols and can be targeted by sterol biosynthesis inhibitors. Here, we characterized sterol 14-demethylase, including catalytic properties and inhibition by clinical antifungal drugs and experimental substituted azoles with favorable pharmacokinetics and low toxicity. None of them inhibited the enzyme stoichiometrically. The highest potencies were displayed by posaconazole (IC = 0.69 μM) and two of our compounds (IC = 1.3 and 0.35 μM). Because both these compounds penetrate the brain with concentrations reaching minimal inhibitory concentration (MIC) values in an cellular assay, we report them as potential drug candidates for PAM. The 2.1 Å crystal structure, in complex with the strongest inhibitor, provides an explanation connecting the enzyme weaker substrate specificity with lower sensitivity to inhibition. It also provides insight into the enzyme/ligand molecular recognition process and suggests directions for the design of more potent inhibitors. PubMed: 34842434DOI: 10.1021/acs.jmedchem.1c01710 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.11 Å) |
Structure validation
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