De novo design of a transmembrane Zn2+-transporting four-helix bundle

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Science  19 Dec 2014:
Vol. 346, Issue 6216, pp. 1520-1524
DOI: 10.1126/science.1261172

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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 Zn2+ and Co2+, but not Ca2+, 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 Zn2+ ions diffuse down their concentration gradients, protons are antiported. These experiments illustrate the feasibility of designing membrane proteins with predefined structural and dynamic properties.

Building transmembrane zinc transporters

The ability to design proteins gives insight into the relation between a protein's fold and its function and also provides a path to custom proteins for bioengineering applications. Impressive strides have been made in the design of soluble proteins, but designing membrane proteins remains a challenge. Joh et al. achieve a milestone by designing a transmembrane Zn2+ transporter (see the Perspective by Lupas). The protein comprises four helices: Two tightly interacting pairs form a weaker interface that facilitates the transport of Zn2+ with concomitant reverse transport of protons.

Science, this issue p. 1520; see also p. 1455

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