6C99

Crystal structure of FcRn bound to UCB-303

6C99 の概要

• エントリーDOI: 10.2210/pdb6c99/pdb
• 分子名称: IgG receptor FcRn large subunit p51, Beta-2-microglobulin, methyl 7-(3,5-difluorophenyl)-5-(pyridin-3-yl)[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate, ... (7 entities in total)
• 機能のキーワード: neonatal fc receptor, fcrn, inhibitor, beta 2 microglobulin, b2m, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 85920.95

構造登録者

Fox III, D.,Abendroth, J.,Porter, J.,Deboves, H. (登録日: 2018-01-25, 公開日: 2018-05-30, 最終更新日: 2024-11-06)

主引用文献

Stoppler, D.,Macpherson, A.,Smith-Penzel, S.,Basse, N.,Lecomte, F.,Deboves, H.,Taylor, R.D.,Norman, T.,Porter, J.,Waters, L.C.,Westwood, M.,Cossins, B.,Cain, K.,White, J.,Griffin, R.,Prosser, C.,Kelm, S.,Sullivan, A.H.,Fox, D.,Carr, M.D.,Henry, A.,Taylor, R.,Meier, B.H.,Oschkinat, H.,Lawson, A.D.
Insight into small molecule binding to the neonatal Fc receptor by X-ray crystallography and 100 kHz magic-angle-spinning NMR.
PLoS Biol., 16:e2006192-e2006192, 2018

PubMed 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.

PubMed: 29782488
DOI: 10.1371/journal.pbio.2006192

実験手法

X-RAY DIFFRACTION (2 Å)