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

Stöppler, Daniel; Macpherson, Alex; Smith-Penzel, Susanne; Basse, Nicolas; Lecomte, Fabien; Deboves, Hervé; Taylor, Richard D.; Norman, Tim; Porter, John; Waters, Lorna C.; Westwood, Marta; Cossins, Ben; Cain, Katharine; White, James; Griffin, Robert; Prosser, Christine; Kelm, Sebastian; Sullivan, Amy H.; Fox III, David; Carr, Mark D.; Henry, Alistair; Taylor, Richard; Meier, Beat H.; Oschkinat, Hartmut; Lawson, Alastair D.

doi:10.1371/journal.pbio.2006192

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

Journal Article · Mon May 21 00:00:00 EDT 2018 · PLoS Biology (Online)

DOI:https://doi.org/10.1371/journal.pbio.2006192· OSTI ID:1499751

^[1]; Macpherson, Alex ^[2]; Smith-Penzel, Susanne ^[3]; Basse, Nicolas ^[4]; Lecomte, Fabien ^[2]; Deboves, Hervé ^[5]; Taylor, Richard D. ^[2]; Norman, Tim ^[2]; Porter, John ^[6]; Waters, Lorna C. ^[7]; Westwood, Marta ^[2]; Cossins, Ben ^[2]; Cain, Katharine ^[8]; White, James ^[2]; Griffin, Robert ^[2]; Prosser, Christine ^[2]; Kelm, Sebastian ^[2]; Sullivan, Amy H. ^[9]; Fox III, David ^[9]; Carr, Mark D. ^[7] more »

Leibniz-Forschungsinstitut fur Molekulare Pharmakologie, Berlin (Germany)
UCB Celltech, Slough (United Kingdom)
ETH Zurich (Switzerland)
Sanofi, Strasbourg (France)
Evotec, Milton (United Kingdom)
Midatech Pharma Plc, Milton (United Kingdom)
Univ. of Leicester (United Kingdom)
Vertex, Milton (United Kingdom)
Beryllium Discovery, Bedford, MA (United States)

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 FcRn_ECD–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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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE; German Research Foundation (DFG); iNEXT; Swiss National Science Foundation (SNF); European Research Council (ERC)

Grant/Contract Number:: SFB 1078 B1; WP1; 200020_159707; 200020_146757; 741863, FASTER

OSTI ID:: 1499751

Journal Information:: PLoS Biology (Online), Vol. 16, Issue 5; ISSN 1545-7885

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 21 works

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Characterization of H ₂ -Splitting Products of Frustrated Lewis Pairs: Benefit of Fast Magic-Angle Spinning Malär, Alexander A.; Dong, Shunxi; Kehr, Gerald ChemPhysChem, Vol. 20, Issue 5 https://doi.org/10.1002/cphc.201900006	journal	February 2019

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59 BASIC BIOLOGICAL SCIENCES
Fc receptors
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