5FRB
Crystal structure of sterol 14-alpha demethylase (CYP51B) from a pathogenic filamentous fungus Aspergillus fumigatus in complex with a tetrazole-based inhibitor VT-1598
Summary for 5FRB
| Entry DOI | 10.2210/pdb5frb/pdb |
| Descriptor | STEROL 14-ALPHA DEMETHYLASE, CYP51B, PROTOPORPHYRIN IX CONTAINING FE, (R)-4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)benzonitrile (3 entities in total) |
| Functional Keywords | sterol 14-alpha demethylase (cyp51), cytochrome p450, heme, oxidoreductase, monooxygenase, sterol biosynthesis, eukaryotic membranes, cytochrome p450 fold, endoplasmic reticulum membrane, oxidoreductase-oxidoreductase inhibitor complex |
| Biological source | ASPERGILLUS FUMIGATUS |
| Total number of polymer chains | 1 |
| Total formula weight | 54784.29 |
| Authors | Hargrove, T.Y.,Wawrzak, Z.,Lepesheva, G.I. (deposition date: 2015-12-16, release date: 2017-04-26, Last modification date: 2024-01-10) |
| Primary citation | Hargrove, T.Y.,Garvey, E.P.,Hoekstra, W.J.,Yates, C.M.,Wawrzak, Z.,Rachakonda, G.,Villalta, F.,Lepesheva, G.I. Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14 alpha-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity. Antimicrob. Agents Chemother., 61:-, 2017 Cited by PubMed Abstract: Within the past few decades, the incidence and complexity of human fungal infections have increased, and therefore, the need for safer and more efficient, broad-spectrum antifungal agents is high. In the study described here, we characterized the new tetrazole-based drug candidate VT-1598 as an inhibitor of sterol 14α-demethylase (CYP51B) from the filamentous fungus VT-1598 displayed a high affinity of binding to the enzyme in solution (dissociation constant, 13 ± 1 nM) and in the reconstituted enzymatic reaction was revealed to have an inhibitory potency stronger than the potencies of all other simultaneously tested antifungal drugs, including fluconazole, voriconazole, ketoconazole, and posaconazole. The X-ray structure of the VT-1598/ CYP51 complex was determined and depicts the distinctive binding mode of the inhibitor in the enzyme active site, suggesting the molecular basis of the improved drug potency and broad-spectrum antifungal activity. These data show the formation of an optimized hydrogen bond between the phenoxymethyl oxygen of VT-1598 and the imidazole ring nitrogen of His374, the CYP51 residue that is highly conserved across fungal pathogens and fungus specific. Comparative structural analysis of CYP51/voriconazole and CYP51/VT-1161 complexes supports the role of H bonding in fungal CYP51/inhibitor complexes and emphasizes the importance of an optimal distance between this interaction and the inhibitor-heme iron interaction. Cellular experiments using two strains (strains 32820 and 1022) displayed a direct correlation between the effects of the drugs on CYP51B activity and fungal growth inhibition, indicating the noteworthy anti- potency of VT-1598 and confirming its promise as a broad-spectrum antifungal agent. PubMed: 28461309DOI: 10.1128/AAC.00570-17 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.99 Å) |
Structure validation
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