Structure of a Pancreatic ATP-Sensitive Potassium Channel

Li, Ningning; Wu, Jing-Xiang; Ding, Dian; Cheng, J.; Gao, Ning; Chen, Lei

doi:10.1016/j.cell.2016.12.028

Cited by 222 publications

(314 citation statements)

References 61 publications

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“…Many ABC family members translocate lipids or lipid-related compounds, including twenty of the 48 human ABC transporters 17 . Despite the growing number of ABC transporter structures determined by crystallography 18,19 and cryo-electron microscopy (cryo-EM) 20–25 , none of these structures revealed a lipid substrate.…”

mentioning

confidence: 99%

Structural basis of MsbA-mediated lipopolysaccharide transport

Yoon

et al. 2017

Nature

230

294

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Lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria is critical for their cell envelope assembly. LPS synthesized in the cytoplasmic leaflet of the inner membrane is flipped to the periplasmic leaflet by MsbA, an ATP-binding cassette transporter. Despite substantial efforts, the structural mechanisms underlying MsbA-driven LPS flipping remain elusive. Here, we use single-particle cryo-EM to elucidate the structures of lipid nanodisc-embedded MsbA in three functional states. The 4.2 Å-resolution structure of the transmembrane domains of nucleotide-free MsbA reveals that LPS binds deeply inside MsbA at the height of the periplasmic leaflet, establishing extensive hydrophilic and hydrophobic interactions with MsbA. Two subnanometer-resolution structures of MsbA with ADP-vanadate and ADP reveal an unprecedented closed and an inward-facing conformation, respectively. Our study uncovers the long-sought-after structural basis for LPS recognition, delineates the conformational transitions of MsbA to flip LPS, and paves the way for structural characterization of other lipid flippases.

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mentioning

confidence: 99%

Structural basis of MsbA-mediated lipopolysaccharide transport

Yoon

et al. 2017

Nature

230

294

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“…Two cryo-electron microscopy structures of the SUR1:Kir6.2 K ATP channels were released at the end of January 2017 with the overall resolution of 5.1 Å [25] (pdb code 5twv) and 5.6Å [26] (pdb code 5wua). The first residue resolved in both structures is R32 however the resolution at this position is not high enough to clearly identify the density of the full length side chain.…”

Section: Resultsmentioning

confidence: 99%

Functional mapping of the N-terminal arginine cluster and C-terminal acidic residues of Kir6.2 channel fused to a G protein-coupled receptor

Principalli

Lemel

Rongier

et al. 2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Ion channel-coupled receptors (ICCRs) are original man-made ligand-gated ion channels created by fusion of G protein-coupled receptors (GPCRs) to the inward-rectifier potassium channel Kir6.2. GPCR conformational changes induced by ligand binding are transduced into electrical current by the ion channel. This functional coupling is closely related to the length of the linker region formed by the GPCR C-terminus (C-ter) and Kir6.2 N-terminus (N-ter). Manipulating the GPCR C-ter length allows to finely tune the channel regulation, both in amplitude and sign (opening or closing Kir6.2). In this work, we demonstrate that the primary sequence of the channel N-terminal domain is an additional parameter for the functional coupling with GPCRs. As for all Kir channels, a cluster of basic residues is present in the N-terminal domain of Kir6.2 and is composed of 5 arginines which are proximal to the GPCR C-ter in the fusion proteins. Using a functional mapping approach, we demonstrate the role of specific arginines (R27 and R32) for the function of ICCRs, indicating that the position and not the cluster of positively-charged arginines is critical for the channel regulation by the GPCR. Following observations provided by molecular dynamics simulation, we explore the hypothesis of interaction of these arginines with acidic residues, and using site-directed mutagenesis, we identified aspartate D307 and glutamate E308 residues as critical for the function of ICCRs. These results demonstrate the critical role of the N-terminal and C-terminal charged residues of Kir6.2 for its allosteric regulation by the fused GPCR.

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“…We now understand these channels well as molecular machines underpinned by exhaustive mutagenesis work and more recently by structural studies. Cryo-electron microscopy has shown how ATP binds to the pore-forming subunit and how MgADP interacts with the nucleotide binding domains in the sulphonylurea receptor [83–85]. Despite the initial description of these channels in the heart [86] there are still questions as to their exact physiological role.…”

Section: Katp Channels Underlie Repolarising Currents In the Sa Nodementioning

confidence: 99%

Potassium channels in the sinoatrial node and their role in heart rate control

Aziz

Tinker

2018

Channels

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Potassium currents determine the resting membrane potential and govern repolarisation in cardiac myocytes. Here, we review the various currents in the sinoatrial node focussing on their molecular and cellular properties and their role in pacemaking and heart rate control. We also describe how our recent finding of a novel ATP-sensitive potassium channel population in these cells fits into this picture.

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Structure of a Pancreatic ATP-Sensitive Potassium Channel

Cited by 222 publications

References 61 publications

Structural basis of MsbA-mediated lipopolysaccharide transport

Structural basis of MsbA-mediated lipopolysaccharide transport

Functional mapping of the N-terminal arginine cluster and C-terminal acidic residues of Kir6.2 channel fused to a G protein-coupled receptor

Potassium channels in the sinoatrial node and their role in heart rate control

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