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531 CLC chloride channels: correlating structure with function Raúl Estévez and Thomas J Jentsch* CLC chloride channels form a large gene family that is found in The function of CLC channels is crucial for several bacteria, archae and eukaryotes. Previous mutagenesis studies processes [1?], such as the normal excitability of skeletal on CLC chloride channels, combined with electrophysiology, muscle [2], the transport of salt and water across epithelia strongly supported the theory that these channels form a [3,4??,5], and the acidification of intracellular vesicles [6?–8?]. homodimeric structure with one pore per subunit This is evident from mouse models and human genetic (a ‘double-barrelled’ channel), and also provided clues about diseases. Thus, mutations in ClC-1 cause myotonia gating and permeation. Recently, the crystal structures of two congenita [2], mutations in ClC-5 cause Dent’s disease [9], bacterial CLC proteins have been obtained by X-ray diffraction mutations in ClC-Kb [3] or its β-subunit barttin [4??,10] analysis. They confirm the double-barrelled architecture, and cause Bartter’s syndrome type III or type IV, respectively, reveal a surprisingly complex and unprecedented channel and mutations in ClC-7 underlie recessive [8?] and structure. At its binding site in the pore, chloride interacts with dominant [11] osteopetrosis. the ends of four helices that come from both sides of the membrane. A glutamate residue that protrudes into the pore is In a breakthrough work, the high-resolution crystal proposed to participate in gating. The structure confirms structure of two bacterial CLC proteins was reported several previous conclusions from mutagenesis studies and recently [12??]. In the following article, we review the provides an excellent framework for their interpretation. recent pro