PDBsum entry 6qv6

Membrane protein

PDB id: 6qv6

Contents

Protein chains

469 a.a.

PDB id:

6qv6

Name:

Membrane protein

Title:

Cryoem structure of the human clc-1 chloride channel, membrane domain

Structure:

Chloride channel protein 1. Chain: b, a. Synonym: clc-1,chloride channel protein,skeletal muscle. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: clcn1, clc1. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932

Authors:

K.T.Wang,P.E.Gourdon,Z.H.Zhou

Key ref:

K.Wang et al. (2019). Structure of the human ClC-1 chloride channel. PLoS Biol, 17, e3000218. PubMed id: 31022181 DOI: 10.1371/journal.pbio.3000218

Date:

01-Mar-19 Release date: 08-May-19

Protein chains

P35523  (CLCN1_HUMAN) -  Chloride channel protein 1 from Homo sapiens

Seq: 988 a.a.

Struc: 469 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1371/journal.pbio.3000218

PLoS Biol 17:e3000218 (2019)

PubMed id: 31022181

Structure of the human ClC-1 chloride channel.

K.Wang, S.S.Preisler, L.Zhang, Y.Cui, J.W.Missel, C.Grønberg, K.Gotfryd, E.Lindahl, M.Andersson, K.Calloe, P.F.Egea, D.A.Klaerke, M.Pusch, P.A.Pedersen, Z.H.Zhou, P.Gourdon.

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.