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National Institute of General Medical Sciences (NIGMS) and National Cancer Institute (NCI) of the National Institutes of Health (NIH)

A designed ion channel

Chris Miller group (Brandeis University)


Chris Miller's group of Brandeis University studies controlled movement of solutes across biological membranes, which is managed by two types of integral membrane proteins - channels, and transporters. Channels allow for passive diffusion down a thermodynamic gradient, whereas transporters operate by a cycle of conformational changes, usually coupled to energy sources to drive substrates thermodynamically uphill. Accordingly, channel-mediated movement of substrates tends to be orders of magnitude faster than that of transporters. The peculiar CLC family of proteins, which allow the movement of Cl- across membranes in most organisms, has members that are Cl- channels, and members that are Cl-/H+ antiporters. Only the structure of the antiporter has been previously determined. In this creative work, the Miller group performed a kind of "mechanistic metamorphosis" to convert a proton-coupled chloride "antiporter" protein into a chloride channel. They wanted to see if some mutational surgery could "break" the antiporter, by removing putative conformational "gates", and thus turn it into a transmembrane continuous pathway selective for Cl ion. They were successful in this endeavor, and using data obtained at GM/CA-CAT and at beamline X29 of the NSLS, they were able to determine the structure of the mutant. The artificially-designed channel is very narrow, and slow; the authors expect natural CLC channels to have a significantly larger channel.

Figure: Images of the Cl- conduits of the antiporter (left), and the doubly-ungated mutant (right), visualized with the program HOLE.


Jayaram, H, Accardi, A, Wu, F, Williams, C, Miller, C. Ion permeation through a Cl--selective channel designed from a CLC Cl-/H+ exchanger, Proc. Natl. Acad. Sci. USA 105 (32), 11194-11199 (2008). DOI: 10.1073/pnas.0804503105.

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