跨膜锌离子转运四螺旋束的从头设计。
De novo design of a transmembrane Zn²⁺-transporting four-helix bundle.
作者信息
Joh Nathan H, Wang Tuo, Bhate Manasi P, Acharya Rudresh, Wu Yibing, Grabe Michael, Hong Mei, Grigoryan Gevorg, DeGrado William F
机构信息
Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
出版信息
Science. 2014 Dec 19;346(6216):1520-4. doi: 10.1126/science.1261172.
The design of functional membrane proteins from first principles represents a grand challenge in chemistry and structural biology. Here, we report the design of a membrane-spanning, four-helical bundle that transports first-row transition metal ions Zn(2+) and Co(2+), but not Ca(2+), across membranes. The conduction path was designed to contain two di-metal binding sites that bind with negative cooperativity. X-ray crystallography and solid-state and solution nuclear magnetic resonance indicate that the overall helical bundle is formed from two tightly interacting pairs of helices, which form individual domains that interact weakly along a more dynamic interface. Vesicle flux experiments show that as Zn(2+) ions diffuse down their concentration gradients, protons are antiported. These experiments illustrate the feasibility of designing membrane proteins with predefined structural and dynamic properties.
从第一性原理出发设计功能性膜蛋白是化学和结构生物学领域的一项重大挑战。在此，我们报告了一种跨膜四螺旋束的设计，该四螺旋束能够跨膜运输第一排过渡金属离子Zn(2+)和Co(2+)，但不能运输Ca(2+)。传导路径被设计为包含两个具有负协同性结合的双金属结合位点。X射线晶体学、固态和溶液核磁共振表明，整个螺旋束由两对紧密相互作用的螺旋形成，这两对螺旋形成了沿着更动态界面弱相互作用的单个结构域。囊泡通量实验表明，随着Zn(2+)离子沿其浓度梯度扩散，质子被反向转运。这些实验说明了设计具有预定义结构和动态特性的膜蛋白的可行性。
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