ArticleAnalytical chemistry2017
Click Chemistry Reagent for Identification of Sites of Covalent Ligand Incorporation in Integral Membrane Proteins.
Article in Analytical chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 21 citations in OpenAlex.
- Article
- E as in Enigma: The Mysterious Role of the Voltage-Dependent Anion Channel Glutamate E73.International journal of molecular sciences · 2022Review
- Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites.eLife · 2022Article
- Article
- VDAC regulation of mitochondrial calcium flux: From channel biophysics to disease.Cell calcium · 2021Review
- Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels.Frontiers in physiology · 2021Review
- Multiple neurosteroid and cholesterol binding sites in voltage-dependent anion channel-1 determined by photo-affinity labeling.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2019Article
- Multiple functional neurosteroid binding sites on GABAA receptors.PLoS biology · 2019Article
- Common binding sites for cholesterol and neurosteroids on a pentameric ligand-gated ion channel.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2019Article
- Assessing the role of residue E73 and lipid headgroup charge in VDAC1 voltage gating.Biochimica et biophysica acta. Bioenergetics · 2019Article
- Mapping two neurosteroid-modulatory sites in the prototypic pentameric ligand-gated ion channel GLIC.The Journal of biological chemistry · 2018Article
- The Role of Electron Transfer Dissociation in Modern Proteomics.Analytical chemistry · 2018Review
- A Clickable Oxysterol Photolabel Retains NMDA Receptor Activity and Accumulates in Neurons.Frontiers in neuroscience · 2018Article
- Photoaffinity labeling with cholesterol analogues precisely maps a cholesterol-binding site in voltage-dependent anion channel-1.The Journal of biological chemistry · 2017Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
Identifying sites of protein-ligand interaction is important for structure-based drug discovery and understanding protein structure-function relationships. Mass spectrometry (MS) has emerged as a useful tool for identifying residues covalently modified by ligands. Current methods use database searches that are dependent on acquiring interpretable fragmentation spectra (MS2) of peptide-ligand adducts. This is problematic for identifying sites of hydrophobic ligand incorporation in integral membrane proteins (IMPs), where poor aqueous solubility and ionization of peptide-ligand adducts and collision-induced adduct loss hinder the acquisition of quality MS2 spectra. To address these issues, we developed a fast ligand identification (FLI) tag that can be attached to any alkyne-containing ligand via Cu(I)-catalyzed cycloaddition. The FLI tag adds charge to increase solubility and ionization, and utilizes stable isotope labeling for MS1 level identification of hydrophobic peptide-ligand adducts. The FLI tag was coupled to an alkyne-containing neurosteroid photolabeling reagent and used to identify peptide-steroid adducts in MS1 spectra via the stable heavy isotope pair. Peptide-steroid adducts were not identified in MS2-based database searches because collision-induced adduct loss was the dominant feature of collision-induced dissociation (CID) fragmentation, but targeted analysis of MS1 pairs using electron transfer dissociation (ETD) markedly reduced adduct loss. Using the FLI tag and ETD, we identified Glu73 as the site of photoincorporation of our neurosteroid ligand in the IMP, mouse voltage-dependent anion channel-1 (mVDAC1), and top-down MS confirmed a single site of photolabeling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.