3UKN

Structure of the C-linker/CNBHD of zELK channels in C 2 2 21 space group

Summary for 3UKN

• Entry DOI: 10.2210/pdb3ukn/pdb
• Related: 3UK5 3UKT 3UKV
• Descriptor: Novel protein similar to vertebrate potassium voltage-gated channel, subfamily H (Eag-related) family (2 entities in total)
• Functional Keywords: kcnh, elk, erg, eag, cnbd, cnbhd, c-linker, ion channel, cyclic nucleotide, cyclic nucleotide-binding domain, ion transport, transport protein, membrane protein
• Biological source: Danio rerio (leopard danio,zebra danio,zebra fish)
• Total number of polymer chains: 3
• Total formula weight: 72215.35

Authors

Brelidze, T.I. (deposition date: 2011-11-09, release date: 2012-01-04, Last modification date: 2024-04-03)

Primary citation

Brelidze, T.I.,Carlson, A.E.,Sankaran, B.,Zagotta, W.N.
Structure of the carboxy-terminal region of a KCNH channel.
Nature, 481:530-533, 2012

PubMed Abstract: The KCNH family of ion channels, comprising ether-à-go-go (EAG), EAG-related gene (ERG), and EAG-like (ELK) K(+)-channel subfamilies, is crucial for repolarization of the cardiac action potential, regulation of neuronal excitability and proliferation of tumour cells. The carboxy-terminal region of KCNH channels contains a cyclic-nucleotide-binding homology domain (CNBHD) and C-linker that couples the CNBHD to the pore. The C-linker/CNBHD is essential for proper function and trafficking of ion channels in the KCNH family. However, despite the importance of the C-linker/CNBHD for the function of KCNH channels, the structural basis of ion-channel regulation by the C-linker/CNBHD is unknown. Here we report the crystal structure of the C-linker/CNBHD of zebrafish ELK channels at 2.2-Å resolution. Although the overall structure of the C-linker/CNBHD of ELK channels is similar to the cyclic-nucleotide-binding domain (CNBD) structure of the related hyperpolarization-activated cyclic-nucleotide-modulated (HCN) channels, there are marked differences. Unlike the CNBD of HCN, the CNBHD of ELK displays a negatively charged electrostatic profile that explains the lack of binding and regulation of KCNH channels by cyclic nucleotides. Instead of cyclic nucleotide, the binding pocket is occupied by a short β-strand. Mutations of the β-strand shift the voltage dependence of activation to more depolarized voltages, implicating the β-strand as an intrinsic ligand for the CNBHD of ELK channels. In both ELK and HCN channels the C-linker is the site of virtually all of the intersubunit interactions in the C-terminal region. However, in the zebrafish ELK structure there is a reorientation in the C-linker so that the subunits form dimers instead of tetramers, as observed in HCN channels. These results provide a structural framework for understanding the regulation of ion channels in the KCNH family by the C-linker/CNBHD and may guide the design of specific drugs.

PubMed: 22230959
DOI: 10.1038/nature10735

Experimental method

X-RAY DIFFRACTION (2.2 Å)