De Novo-Designed α-Helical Barrels as Receptors for Small Molecules.
De Novo-Designed α-Helical Barrels as Receptors for Small Molecules.
复制标题
De Novo 设计的 α-螺旋桶作为小分子的受体。
作者：
F. Thomas;W. Dawson;Eric J. M. Lang;A. Burton;G. J. Bartlett;G. G. Rhys;A. Mulholland;D. Woolfson
我们描述了从头设计的α-螺旋桶（αHBs），它结合并区分亲脂性生物活性分子。 αHB 具有五个或更多排列在中心疏水通道周围的 α 螺旋，其直径与寡聚物状态成比例。我们发现五聚体、六聚体和七聚体 αHB 在微摩尔范围内与环境敏感染料 1,6-二苯基六三烯 (DPH) 结合并发出荧光。染料的置换用于报告非荧光分子的结合：棕榈酸和视黄醇以亚微摩尔抑制剂常数与所有三种 αHB 结合；金合欢醇结合六聚体和七聚体；但β-胡萝卜素仅结合七聚体。六聚体与金合欢醇的共晶结构揭示了疏水通道中心的定向结合。设计到七聚体内腔的带电侧链有助于极性配体的结合：谷氨酸变体结合 DPH 的阳离子变体，引入赖氨酸可以结合生物合成重要的法尼醇二磷酸盐。
We describe de novo-designed α-helical barrels (αHBs) that bind and discriminate between lipophilic biologically active molecules. αHBs have five or more α-helices arranged around central hydrophobic channels the diameters of which scale with oligomer state. We show that pentameric, hexameric, and heptameric αHBs bind the environmentally sensitive dye 1,6-diphenylhexatriene (DPH) in the micromolar range and fluoresce. Displacement of the dye is used to report the binding of nonfluorescent molecules: palmitic acid and retinol bind to all three αHBs with submicromolar inhibitor constants; farnesol binds the hexamer and heptamer; but β-carotene binds only the heptamer. A co-crystal structure of the hexamer with farnesol reveals oriented binding in the center of the hydrophobic channel. Charged side chains engineered into the lumen of the heptamer facilitate binding of polar ligands: a glutamate variant binds a cationic variant of DPH, and introducing lysine allows binding of the biosynthetically important farnesol diphosphate.
登录
查看更多内容
影响因子：
2.9
作者：
Albuquerque P;Casadevall A
通讯作者：
Casadevall A
影响因子：
5.6
作者：
Grigoryan G;Degrado WF
通讯作者：
Degrado WF
影响因子：
56.9
作者：
Harbury, PB;Plecs, JJ;Kim, PS
通讯作者：
Kim, PS
影响因子：
2.9
作者：
Yadav,ManeeshK;Redman,JamesE;Leman,LukeJ;Alvarez-Gutiérrez,JuliettaM;Zhang,Yanming;Stout,CDavid;Ghadiri,MReza
通讯作者：
Ghadiri,MReza
影响因子：
4.7
作者：
Fletcher, Jordan M.;Boyle, Aimee L.;Woolfson, Derek N.
通讯作者：
Woolfson, Derek N.