4CKA
STEROL 14-ALPHA DEMETHYLASE (CYP51)FROM TRYPANOSOMA CRUZI IN COMPLEX WITH (S)-1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl 4- isopropylphenylcarbamate (LFS)
Summary for 4CKA
| Entry DOI | 10.2210/pdb4cka/pdb |
| Related | 4CK8 4CK9 |
| Descriptor | STEROL 14-ALPHA DEMETHYLASE, PROTOPORPHYRIN IX CONTAINING FE, (1S)-1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl 4-isopropylphenylcarbamate, ... (4 entities in total) |
| Functional Keywords | heme, oxidoreductase, monooxygenase, sterol biosynthesis, eukaryotic membranes, cytochrome p450 fold, endoplasmic reticulum membrane |
| Biological source | TRYPANOSOMA CRUZI |
| Cellular location | Membrane; Single-pass membrane protein (Potential): Q7Z1V1 |
| Total number of polymer chains | 1 |
| Total formula weight | 53536.80 |
| Authors | Friggeri, L.,Wawrzak, Z.,Tortorella, S.,Lepesheva, G.I. (deposition date: 2013-12-31, release date: 2014-07-30, Last modification date: 2023-12-20) |
| Primary citation | Friggeri, L.,Hargrove, T.Y.,Rachakonda, G.,Williams, A.D.,Wawrzak, Z.,Di Santo, R.,De Vita, D.,Waterman, M.R.,Tortorella, S.,Villalta, F.,Lepesheva, G.I. Structural Basis for Rational Design of Inhibitors Targeting Trypanosoma Cruzi Sterol 14Alpha-Demethylase: Two Regions of the Enzyme Molecule Potentiate its Inhibition. J.Med.Chem., 57:6704-, 2014 Cited by PubMed Abstract: Chagas disease, which was once thought to be confined to endemic regions of Latin America, has now gone global, becoming a new worldwide challenge with no cure available. The disease is caused by the protozoan parasite Trypanosoma cruzi, which depends on the production of endogenous sterols, and therefore can be blocked by sterol 14α-demethylase (CYP51) inhibitors. Here we explore the spectral binding parameters, inhibitory effects on T. cruzi CYP51 activity, and antiparasitic potencies of a new set of β-phenyl imidazoles. Comparative structural characterization of the T. cruzi CYP51 complexes with the three most potent inhibitors reveals two opposite binding modes of the compounds ((R)-6, EC50=1.2 nM, vs (S)-2/(S)-3, EC50=1.0/5.5 nM) and suggests the entrance into the CYP51 substrate access channel and the heme propionate-supporting ceiling of the binding cavity as two distinct areas of the protein that enhance molecular recognition and therefore could be used for the development of more effective antiparasitic drugs. PubMed: 25033013DOI: 10.1021/JM500739F PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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