ArticleBiochimica et biophysica acta2012
NMR structure and dynamics of a designed water-soluble transmembrane domain of nicotinic acetylcholine receptor.
Article in Biochimica et biophysica acta, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Engineering of soluble bacteriorhodopsin.Chemical science · 2025Article
- Design of a water-soluble transmembrane receptor kinase with intact molecular function by QTY code.Nature communications · 2024Article
- Protein Design: From the Aspect of Water Solubility and Stability.Chemical reviews · 2022Review
- Dawn of a New Era for Membrane Protein Design.Biodesign research · 2022Review
- QTY code enables design of detergent-free chemokine receptors that retain ligand-binding activities.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Solution NMR Studies of Anesthetic Interactions with Ion Channels.Methods in enzymology · 2018Article
- Molecular mechanism of anesthetic-induced depression of myocardial contraction.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2016Article
- Membrane proteins: always an insoluble problem?Biochemical Society transactions · 2016Review
- Anesthetics target interfacial transmembrane sites in nicotinic acetylcholine receptors.Neuropharmacology · 2015Review
- Characterization of a computationally designed water-soluble human μ-opioid receptor variant using available structural information.Anesthesiology · 2014Article
- Scalable production of highly sensitive nanosensors based on graphene functionalized with a designed G protein-coupled receptor.Nano letters · 2014Article
- Mechanisms revealed through general anesthetic photolabeling.Current anesthesiology reports · 2014Article
- Assessment of homology templates and an anesthetic binding site within the γ-aminobutyric acid receptor.Anesthesiology · 2013Article
- Experimental determination of the vertical alignment between the second and third transmembrane segments of muscle nicotinic acetylcholine receptors.Journal of neurochemistry · 2013Article
- NMR resolved multiple anesthetic binding sites in the TM domains of the α4β2 nAChR.Biochimica et biophysica acta · 2013Article
- In vivo activation of azipropofol prolongs anesthesia and reveals synaptic targets.The Journal of biological chemistry · 2013Article
- A computationally designed water-soluble variant of a G-protein-coupled receptor: the human mu opioid receptor.PloS one · 2013Article
- Computational design of membrane proteins.Structure (London, England : 1993) · 2012Review
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13 authors.
Funding
Abstract
The nicotinic acetylcholine receptor (nAChR) is an important therapeutic target for a wide range of pathophysiological conditions, for which rational drug designs often require receptor structures at atomic resolution. Recent proof-of-concept studies demonstrated a water-solubilization approach to structure determination of membrane proteins by NMR (Slovic et al., PNAS, 101: 1828-1833, 2004; Ma et al., PNAS, 105: 16537-42, 2008). We report here the computational design and experimental characterization of WSA, a water-soluble protein with ~83% sequence identity to the transmembrane (TM) domain of the nAChR α1 subunit. Although the design was based on a low-resolution structural template, the resulting high-resolution NMR structure agrees remarkably well with the recent crystal structure of the TM domains of the bacterial Gloeobacter violaceus pentameric ligand-gated ion channel (GLIC), demonstrating the robustness and general applicability of the approach. NMR T(2) dispersion measurements showed that the TM2 domain of the designed protein was dynamic, undergoing conformational exchange on the NMR timescale. Photoaffinity labeling with isoflurane and propofol photolabels identified a common binding site in the immediate proximity of the anesthetic binding site found in the crystal structure of the anesthetic-GLIC complex. Our results illustrate the usefulness of high-resolution NMR analyses of water-solubilized channel proteins for the discovery of potential drug binding sites.
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