High-Resolution Cryoelectron Microscopy Structure of the Cyclic Nucleotide-Modulated Potassium Channel MloK1 in a Lipid Bilayer.

Eukaryotic cyclic nucleotide-modulated channels perform their diverse physiological roles by opening and closing their pores to ions in response to cyclic nucleotide binding. We here present a structural model for the cyclic nucleotide-modulated potassium channel homolog from Mesorhizobium loti, MloK1, determined from 2D crystals in the presence of lipids. Even though crystals diffract electrons to only ∼10 Å, using cryoelectron microscopy (cryo-EM) and recently developed computational methods, we have determined a 3D map of full-length MloK1 in the presence of cyclic AMP (cAMP) at ∼4.5 Å isotropic 3D resolution. The structure provides a clear picture of the arrangement of the cyclic nucleotide-binding domains with respect to both the pore and the putative voltage sensor domains when cAMP is bound, and reveals a potential gating mechanism in the context of the lipid-embedded channel.

Kowal J ，Biyani N ，Chami M ，Scherer S ，Rzepiela AJ ，Baumgartner P ，Upadhyay V ，Nimigean CM ，Stahlberg H ... -  《-》

The structure of the apo cAMP-binding domain of HCN4 - a stepping stone toward understanding the cAMP-dependent modulation of the hyperpolarization-activated cyclic-nucleotide-gated ion channels.

The hyperpolarization-activated cyclic-nucleotide-gated (HCN) ion channels control nerve impulse transmission and cardiac pacemaker activity. The modulation by cAMP is critical for the regulatory function of HCN in both neurons and cardiomyocytes, but the underlying mechanism is not fully understood. Here, we show how the structure of the apo cAMP-binding domain of the HCN4 isoform has contributed to a model for the cAMP-dependent modulation of the HCN ion-channel. This model recapitulates the structural and dynamical changes that occur along the thermodynamic cycle arising from the coupling of cAMP-binding and HCN self-association equilibria. The proposed model addresses some of the questions previously open about the auto-inhibition of HCN and its cAMP-induced activation, while opening new opportunities for selectively targeting HCN through allosteric ligands. A remaining challenge is the investigation of HCN dimers and their regulatory role. Overcoming this challenge will require the integration of crystallography, cryo electron microscopy, NMR, electrophysiology and simulations.

Akimoto M ，VanSchouwen B ，Melacini G 《-》

A KcsA/MloK1 chimeric ion channel has lipid-dependent ligand-binding energetics.

McCoy JG ，Rusinova R ，Kim DM ，Kowal J ，Banerjee S ，Jaramillo Cartagena A ，Thompson AN ，Kolmakova-Partensky L ，Stahlberg H ，Andersen OS ，Nimigean CM ... -  《-》

Ligand-induced structural changes in the cyclic nucleotide-modulated potassium channel MloK1.

Kowal J ，Chami M ，Baumgartner P ，Arheit M ，Chiu PL ，Rangl M ，Scheuring S ，Schröder GF ，Nimigean CM ，Stahlberg H ... -  《Nature Communications》

The structure of the prokaryotic cyclic nucleotide-modulated potassium channel MloK1 at 16 A resolution.

Chiu PL ，Pagel MD ，Evans J ，Chou HT ，Zeng X ，Gipson B ，Stahlberg H ，Nimigean CM ... -  《STRUCTURE》