%0 Journal Article
%T Structure of the connexin-43 gap junction channel in a putative closed state.
%A Qi C
%A Acosta Gutierrez S
%A Lavriha P
%A Othman A
%A Lopez-Pigozzi D
%A Bayraktar E
%A Schuster D
%A Picotti P
%A Zamboni N
%A Bortolozzi M
%A Gervasio FL
%A Korkhov VM
%J Elife
%V 12
%N 0
%D 2023 08 3
%M 37535063
%F 8.713
%R 10.7554/eLife.87616
%X Gap junction channels (GJCs) mediate intercellular communication by connecting two neighbouring cells and enabling direct exchange of ions and small molecules. Cell coupling via connexin-43 (Cx43) GJCs is important in a wide range of cellular processes in health and disease (Churko and Laird, 2013; Liang et al., 2020; Poelzing and Rosenbaum, 2004), yet the structural basis of Cx43 function and regulation has not been determined until now. Here, we describe the structure of a human Cx43 GJC solved by cryo-EM and single particle analysis at 2.26 Å resolution. The pore region of Cx43 GJC features several lipid-like densities per Cx43 monomer, located close to a putative lateral access site at the monomer boundary. We found a previously undescribed conformation on the cytosolic side of the pore, formed by the N-terminal domain and the transmembrane helix 2 of Cx43 and stabilized by a small molecule. Structures of the Cx43 GJC and hemichannels (HCs) in nanodiscs reveal a similar gate arrangement. The features of the Cx43 GJC and HC cryo-EM maps and the channel properties revealed by molecular dynamics simulations suggest that the captured states of Cx43 are consistent with a closed state.