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bioRxiv · 10.1101/2024.12.25.630309

Accurate de novo design of a voltage-gated anion channel

Zhou, C.·Li, H.·Wang, J.·Chu, Z.·Sun, S.·Sun, K.·Zhu, A.·Jin, X.·Yang, F.·El-Din, T. M. G.·Wu, K.·Lu, P.
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Abstract

Ion channels gated by environmental cues play key roles in fundamental biological processes. Designing ion channels with tailored gating mechanisms remains a significant challenge due to the complexities involved in designing conformational changes in proteins. Here we report the accurate de novo design of a voltage-gated anion channel, namely VGAC. VGAC adopts a 15-helix pentameric structure featuring a constriction composed of five arginine residues within the transmembrane span. In patch-clamp experiments, VGAC showed strictly voltage-dependent currents and demonstrated selectivity for chloride anions over iodide anions. Our data suggests that the arginine constriction undergoes voltage-induced conformational changes, serving as both the voltage sensor and selectivity filter. A 2.9-[A]-resolution cryo-electron microscopy structure of VGAC closely aligns with the design model. The ability to design ion channels with custom-designed conformational changes provides new insights into our understanding of the fundamental principles of membrane biophysics and unveils a wide range of potential applications.

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Zhou, C., Li, H., Wang, J., Chu, Z., Sun, S., Sun, K., Zhu, A., Jin, X., Yang, F., El-Din, T. M. G., Wu, K., Lu, P.. 2024-12-25. Accurate de novo design of a voltage-gated anion channel. https://doi.org/10.1101/2024.12.25.630309

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