Insight into small molecule binding to the neonatal Fc receptor by X-ray crystallography and 100 kHz magic-angle-spinning NMR

PLoS Biology
Daniel StöpplerAlastair D Lawson

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 int...Continue Reading

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Citations

Jan 22, 2019·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Alexander A MalärThomas Wiegand
Jul 17, 2019·Chembiochem : a European Journal of Chemical Biology·Thomas WiegandAnja Böckmann
Dec 19, 2019·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Sungsool Wi, Lucio Frydman
Aug 10, 2019·Frontiers in Molecular Biosciences·Lauriane LecoqAnja Böckmann
Mar 19, 2020·Journal of Biomolecular NMR·Daniel FriedrichHartmut Oschkinat
Mar 11, 2020·Frontiers in Molecular Biosciences·Thomas WiegandAnja Böckmann
Dec 12, 2020·International Journal of Molecular Sciences·Shingo KanemuraMasaki Okumura
May 31, 2020·Progress in Nuclear Magnetic Resonance Spectroscopy·Thomas Wiegand
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Nov 27, 2020·The Journal of Physical Chemistry. B·Denis LacabanneThomas Wiegand
Sep 8, 2021·Nature Communications·Alexander A MalärThomas Wiegand
Oct 26, 2021·Chemical Reviews·Alexander A ShcherbakovMei Hong

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Methods Mentioned

BETA
NMR
ELISA
in silico methods
X-ray
Surface Plasmon Resonance
FRET
glycosylation
Gel Filtration
Chip
transfection

Software Mentioned

Crystallographic Object - Oriented Toolkit ( COOT
Bruker
MEDELLER
XSCALE
Phenix
OrthoDB
GROMACS
Molprobity
SEDFIT
GeneComposer

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