![]() ![]() The CTD extends the ion conduction pathway and provides docking sites for regulatory ions, proteins, and ligands ( 2). They have a canonical pore-forming transmembrane domain (TMD) made of two transmembrane helices (M1 and M2) separated by a K + ion selectivity filter and a large cytoplasmic domain (CTD) containing both N and C termini. Our results revealed structural features unique to human Kir2.1 and provided insights into the connection between G-loop and gating and the pathological mechanisms associated with this channel.Īll Kir channels are tetramers of identical or related subunits and share characteristic structural features. In addition, molecular dynamics simulations and normal mode analysis showed the intrinsic tendency of the CTD to tether to the TMD and a movement of the secondary anionic binding site to the membrane even without PIP 2. The structural analysis (cryo–electron microscopy), surface plasmon resonance, and electrophysiological experiments revealed a well-connected network of interactions between the PIP 2-binding site and the G-loop through residues R312 and H221. Genetically inherited defects in Kir2.1 channels are responsible for several rare human diseases, including Andersen’s syndrome. Their gating is modulated by phosphatidylinositol 4,5-bisphosphate (PIP 2). Kir2.1 channels are strongly inward-rectifying potassium channels that play a key role in maintaining resting membrane potential. We present the first structure of the human Kir2.1 channel containing both transmembrane domain (TMD) and cytoplasmic domain (CTD). ![]()
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