6F0E

Structure of yeast Sec14p with a picolinamide compound

6F0E の概要

• エントリーDOI: 10.2210/pdb6f0e/pdb
• 分子名称: SEC14 cytosolic factor, ~{N}-(1,3-benzodioxol-5-ylmethyl)-5-bromanyl-3-fluoranyl-pyridine-2-carboxamide (3 entities in total)
• 機能のキーワード: sec14p, lipid transfer protein, chemogenomics, target identification, functional variomics, co-crystal, antifungal, benzamide, picolinamide, lipid binding protein
• 由来する生物種: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast)
• 細胞内の位置: Golgi apparatus membrane; Peripheral membrane protein: P24280
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36401.02

構造登録者

Hong, Z.,Johnen, P.,Schaaf, G.,Bono, F. (登録日: 2017-11-20, 公開日: 2018-01-17, 最終更新日: 2024-01-17)

主引用文献

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

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: 29307839
DOI: 10.1016/j.chembiol.2017.12.007

実験手法

X-RAY DIFFRACTION (2.6 Å)