ArticlePLoS biology2018
Insight into small molecule binding to the neonatal Fc receptor by X-ray crystallography and 100 kHz magic-angle-spinning NMR.
Article in PLoS biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 43 citations in OpenAlex.
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- FcRn-Driven Nanoengineered Mucosal Vaccine with Multi-Epitope Fusion Induces Robust Dual Immunity and Long-Term Protection AgainstVaccines · 2025Article
- Solid-state NMR protocols for unveiling dynamics and (drug) interactions of membrane-bound proteins.Protein science : a publication of the Protein Society · 2025Article
- Analysis of the structure and interactions of the SARS-CoV-2 ORF7b accessory protein.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Sedimentation of large, soluble proteins up to 140 kDa forJournal of biomolecular NMR · 2024Article
- Studying large biomolecules as sedimented solutes with solid-state NMR.Biophysics reports · 2024Article
- Initial Primer Synthesis of a DNA Primase Monitored by Real-Time NMR Spectroscopy.Journal of the American Chemical Society · 2024Article
- High and fast: NMR protein-proton side-chain assignments at 160 kHz and 1.2 GHz.Chemical science · 2023Article
- Mechanism of threonine ADP-ribosylation of F-actin by a Tc toxin.Nature communications · 2022Article
- From Angstroms to Nanometers: Measuring Interatomic Distances by Solid-State NMR.Chemical reviews · 2022Review
- Review
- Spectroscopic glimpses of the transition state of ATP hydrolysis trapped in a bacterial DnaB helicase.Nature communications · 2021Article
- Residual dipolar line width in magic-angle spinning proton solid-state NMR.Magnetic resonance (Gottingen, Germany) · 2021Article
- Protein Side-Chain-DNA Contacts Probed by Fast Magic-Angle Spinning NMR.The journal of physical chemistry. B · 2020Article
- PDI Family Members as Guides for Client Folding and Assembly.International journal of molecular sciences · 2020Review
- MAS NMR detection of hydrogen bonds for protein secondary structure characterization.Journal of biomolecular NMR · 2020Article
- Nucleotide Binding Modes in a Motor Protein Revealed byChembiochem : a European journal of chemical biology · 2020Article
- Sedimentation Yields Long-Term Stable Protein Samples as Shown by Solid-State NMR.Frontiers in molecular biosciences · 2020Article
- Asparagine and Glutamine Side-Chains and Ladders in HET-s(218-289) Amyloid Fibrils Studied by Fast Magic-Angle Spinning NMR.Frontiers in molecular biosciences · 2020Article
- Origin of the residual line width under frequency-switched Lee-Goldburg decoupling in MAS solid-state NMR.Magnetic resonance (Gottingen, Germany) · 2020Article
Corrections and comments
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Authors and funding
25 authors at 9 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aiming at the design of an allosteric modulator of the neonatal Fc receptor (FcRn)-Immunoglobulin G (IgG) interaction, we developed a new methodology including NMR fragment screening, X-ray crystallography, and magic-angle-spinning (MAS) NMR at 100 kHz after sedimentation, exploiting very fast spinning of the nondeuterated soluble 42 kDa receptor construct to obtain resolved proton-detected 2D and 3D NMR spectra. FcRn plays a crucial role in regulation of IgG and serum albumin catabolism. It is a clinically validated drug target for the treatment of autoimmune diseases caused by pathogenic antibodies via the inhibition of its interaction with IgG. We herein present the discovery of a small molecule that binds into a conserved cavity of the heterodimeric, extracellular domain composed of an α-chain and β2-microglobulin (β2m) (FcRnECD, 373 residues). X-ray crystallography was used alongside NMR at 100 kHz MAS with sedimented soluble protein to explore possibilities for refining the compound as an allosteric modulator. Proton-detected MAS NMR experiments on fully protonated [13C,15N]-labeled FcRnECD yielded ligand-induced chemical-shift perturbations (CSPs) for residues in the binding pocket and allosteric changes close to the interface of the two receptor heterodimers present in the asymmetric unit as well as potentially in the albumin interaction site. X-ray structures with and without ligand suggest the need for an optimized ligand to displace the α-chain with respect to β2m, both of which participate in the FcRnECD-IgG interaction site. Our investigation establishes a method to characterize structurally small molecule binding to nondeuterated large proteins by NMR, even in their glycosylated form, which may prove highly valuable for structure-based drug discovery campaigns.
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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.