6F0E
Structure of yeast Sec14p with a picolinamide compound
Summary for 6F0E
| Entry DOI | 10.2210/pdb6f0e/pdb |
| Descriptor | SEC14 cytosolic factor, ~{N}-(1,3-benzodioxol-5-ylmethyl)-5-bromanyl-3-fluoranyl-pyridine-2-carboxamide (3 entities in total) |
| Functional Keywords | sec14p, lipid transfer protein, chemogenomics, target identification, functional variomics, co-crystal, antifungal, benzamide, picolinamide, lipid binding protein |
| Biological source | Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast) |
| Cellular location | Golgi apparatus membrane; Peripheral membrane protein: P24280 |
| Total number of polymer chains | 1 |
| Total formula weight | 36401.02 |
| Authors | Hong, Z.,Johnen, P.,Schaaf, G.,Bono, F. (deposition date: 2017-11-20, release date: 2018-01-17, Last modification date: 2024-01-17) |
| Primary citation | Pries, V.,Nocker, C.,Khan, D.,Johnen, P.,Hong, Z.,Tripathi, A.,Keller, A.L.,Fitz, M.,Perruccio, F.,Filipuzzi, I.,Thavam, S.,Aust, T.,Riedl, R.,Ziegler, S.,Bono, F.,Schaaf, G.,Bankaitis, V.A.,Waldmann, H.,Hoepfner, D. Target Identification and Mechanism of Action of Picolinamide and Benzamide Chemotypes with Antifungal Properties. Cell Chem Biol, 25:279-290.e7, 2018 Cited by PubMed Abstract: Invasive fungal infections are accompanied by high mortality rates that range up to 90%. At present, only three different compound classes are available for use in the clinic, and these often suffer from low bioavailability, toxicity, and drug resistance. These issues emphasize an urgent need for novel antifungal agents. Herein, we report the identification of chemically versatile benzamide and picolinamide scaffolds with antifungal properties. Chemogenomic profiling and biochemical assays with purified protein identified Sec14p, the major phosphatidylinositol/phosphatidylcholine transfer protein in Saccharomyces cerevisiae, as the sole essential target for these compounds. A functional variomics screen identified resistance-conferring residues that localized to the lipid-binding pocket of Sec14p. Determination of the X-ray co-crystal structure of a Sec14p-compound complex confirmed binding in this cavity and rationalized both the resistance-conferring residues and the observed structure-activity relationships. Taken together, these findings open new avenues for rational compound optimization and development of novel antifungal agents. PubMed: 29307839DOI: 10.1016/j.chembiol.2017.12.007 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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