6QVC

CryoEM structure of the human ClC-1 chloride channel, CBS state 1

Summary for 6QVC

• Entry DOI: 10.2210/pdb6qvc/pdb
• Related: 6QV6 6QVB
• EMDB information: 4647
• Descriptor: Chloride channel protein 1 (1 entity in total)
• Functional Keywords: chloride channel, clc1, clcn1, membrane protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 217466.34

Authors

Wang, K.T.,Gourdon, P.E.,Zhou, Z.H. (deposition date: 2019-03-01, release date: 2019-05-08, Last modification date: 2024-05-15)

Primary citation

Wang, K.,Preisler, S.S.,Zhang, L.,Cui, Y.,Missel, J.W.,Gronberg, C.,Gotfryd, K.,Lindahl, E.,Andersson, M.,Calloe, K.,Egea, P.F.,Klaerke, D.A.,Pusch, M.,Pedersen, P.A.,Zhou, Z.H.,Gourdon, P.
Structure of the human ClC-1 chloride channel.
Plos Biol., 17:e3000218-e3000218, 2019

PubMed Abstract: ClC-1 protein channels facilitate rapid passage of chloride ions across cellular membranes, thereby orchestrating skeletal muscle excitability. Malfunction of ClC-1 is associated with myotonia congenita, a disease impairing muscle relaxation. Here, we present the cryo-electron microscopy (cryo-EM) structure of human ClC-1, uncovering an architecture reminiscent of that of bovine ClC-K and CLC transporters. The chloride conducting pathway exhibits distinct features, including a central glutamate residue ("fast gate") known to confer voltage-dependence (a mechanistic feature not present in ClC-K), linked to a somewhat rearranged central tyrosine and a narrower aperture of the pore toward the extracellular vestibule. These characteristics agree with the lower chloride flux of ClC-1 compared with ClC-K and enable us to propose a model for chloride passage in voltage-dependent CLC channels. Comparison of structures derived from protein studied in different experimental conditions supports the notion that pH and adenine nucleotides regulate ClC-1 through interactions between the so-called cystathionine-β-synthase (CBS) domains and the intracellular vestibule ("slow gating"). The structure also provides a framework for analysis of mutations causing myotonia congenita and reveals a striking correlation between mutated residues and the phenotypic effect on voltage gating, opening avenues for rational design of therapies against ClC-1-related diseases.

PubMed: 31022181
DOI: 10.1371/journal.pbio.3000218

Experimental method

ELECTRON MICROSCOPY (4 Å)