7ZGD

Structure of yeast Sec14p with NPPM244

7ZGD の概要

• エントリーDOI: 10.2210/pdb7zgd/pdb
• 分子名称: SEC14 cytosolic factor, (4-bromanyl-3-nitro-phenyl)-[4-(2-fluorophenyl)piperazin-1-yl]methanone (3 entities in total)
• 機能のキーワード: sec14p, nppm244, lipid binding protein
• 由来する生物種: Saccharomyces cerevisiae S288C
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36456.10

構造登録者

Hong, Z.,Johnen, P.,Schaaf, G.,Bono, F. (登録日: 2022-04-03, 公開日: 2023-01-25, 最終更新日: 2024-02-07)

主引用文献

Chen, X.R.,Poudel, L.,Hong, Z.,Johnen, P.,Katti, S.,Tripathi, A.,Nile, A.H.,Green, S.M.,Khan, D.,Schaaf, G.,Bono, F.,Bankaitis, V.A.,Igumenova, T.I.
Mechanisms by which small molecules of diverse chemotypes arrest Sec14 lipid transfer activity.
J.Biol.Chem., 299:102861-102861, 2023

PubMed Abstract: Phosphatidylinositol (PtdIns) transfer proteins (PITPs) enhance the activities of PtdIns 4-OH kinases that generate signaling pools of PtdIns-4-phosphate. In that capacity, PITPs serve as key regulators of lipid signaling in eukaryotic cells. Although the PITP phospholipid exchange cycle is the engine that stimulates PtdIns 4-OH kinase activities, the underlying mechanism is not understood. Herein, we apply an integrative structural biology approach to investigate interactions of the yeast PITP Sec14 with small-molecule inhibitors (SMIs) of its phospholipid exchange cycle. Using a combination of X-ray crystallography, solution NMR spectroscopy, and atomistic MD simulations, we dissect how SMIs compete with native Sec14 phospholipid ligands and arrest phospholipid exchange. Moreover, as Sec14 PITPs represent new targets for the development of next-generation antifungal drugs, the structures of Sec14 bound to SMIs of diverse chemotypes reported in this study will provide critical information required for future structure-based design of next-generation lead compounds directed against Sec14 PITPs of virulent fungi.

PubMed: 36603766
DOI: 10.1016/j.jbc.2022.102861

実験手法

X-RAY DIFFRACTION (2.08 Å)