8EKT
CYP51 from Acanthamoeba castellanii in complex with the tetrazole-based IND inhibitor VT-1161(VT1)
Summary for 8EKT
| Entry DOI | 10.2210/pdb8ekt/pdb |
| Related | 7UWP |
| Descriptor | sterol 14a-demethylase, PROTOPORPHYRIN IX CONTAINING FE, (R)-2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol, ... (4 entities in total) |
| Functional Keywords | cytochrome p450, cyp51, sterol 14alpha-demethylase, sterol biosynthesis, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor |
| Biological source | Acanthamoeba castellanii |
| Total number of polymer chains | 6 |
| Total formula weight | 321547.23 |
| Authors | Hargrove, T.Y.,Wawrzak, Z.,Lepesheva, G.I. (deposition date: 2022-09-21, release date: 2023-08-02, Last modification date: 2024-05-15) |
| Primary citation | Hargrove, T.Y.,Lamb, D.C.,Wawrzak, Z.,Hull, M.,Kelly, S.L.,Guengerich, F.P.,Lepesheva, G.I. Identification of Potent and Selective Inhibitors of Acanthamoeba : Structural Insights into Sterol 14 alpha-Demethylase as a Key Drug Target. J.Med.Chem., 67:7443-7457, 2024 Cited by PubMed Abstract: are free-living pathogenic protozoa that cause blinding keratitis, disseminated infection, and granulomatous amebic encephalitis, which is generally fatal. The development of efficient and safe drugs is a critical unmet need. sterol 14α-demethylase (CYP51) is an essential enzyme of the sterol biosynthetic pathway. Repurposing antifungal azoles for amoebic infections has been reported, but their inhibitory effects on CYP51 enzymatic activity have not been studied. Here, we report catalytic properties, inhibition, and structural characterization of CYP51 from . The enzyme displays a 100-fold substrate preference for obtusifoliol over lanosterol, supporting the plant-like cycloartenol-based pathway in the pathogen. The strongest inhibition was observed with voriconazole (1 h IC 0.45 μM), VT1598 (0.25 μM), and VT1161 (0.20 μM). The crystal structures of CYP51 with bound VT1161 (2.24 Å) and without an inhibitor (1.95 Å), presented here, can be used in the development of azole-based scaffolds to achieve optimal amoebicidal effectiveness. PubMed: 38683753DOI: 10.1021/acs.jmedchem.4c00303 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.29 Å) |
Structure validation
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