6MG4

Structure of full-length human lambda-6A light chain JTO

6MG4 の概要

• エントリーDOI: 10.2210/pdb6mg4/pdb
• 分子名称: JTO light chain (2 entities in total)
• 機能のキーワード: light chain, amyloidosis, immune system
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 46859.64

構造登録者

Morgan, G.J.,Yan, N.L.,Mortenson, D.E.,Stanfield, R.L.,Wilson, I.A.,Kelly, J.W. (登録日: 2018-09-12, 公開日: 2019-04-10, 最終更新日: 2024-11-13)

主引用文献

Morgan, G.J.,Yan, N.L.,Mortenson, D.E.,Rennella, E.,Blundon, J.M.,Gwin, R.M.,Lin, C.Y.,Stanfield, R.L.,Brown, S.J.,Rosen, H.,Spicer, T.P.,Fernandez-Vega, V.,Merlini, G.,Kay, L.E.,Wilson, I.A.,Kelly, J.W.
Stabilization of amyloidogenic immunoglobulin light chains by small molecules.
Proc.Natl.Acad.Sci.USA, 116:8360-8369, 2019

PubMed Abstract: In Ig light-chain (LC) amyloidosis (AL), the unique antibody LC protein that is secreted by monoclonal plasma cells in each patient misfolds and/or aggregates, a process leading to organ degeneration. As a step toward developing treatments for AL patients with substantial cardiac involvement who have difficulty tolerating existing chemotherapy regimens, we introduce small-molecule kinetic stabilizers of the native dimeric structure of full-length LCs, which can slow or stop the amyloidogenicity cascade at its origin. A protease-coupled fluorescence polarization-based high-throughput screen was employed to identify small molecules that kinetically stabilize LCs. NMR and X-ray crystallographic data demonstrate that at least one structural family of hits bind at the LC-LC dimerization interface within full-length LCs, utilizing variable-domain residues that are highly conserved in most AL patients. Stopping the amyloidogenesis cascade at the beginning is a proven strategy to ameliorate postmitotic tissue degeneration.

PubMed: 30971495
DOI: 10.1073/pnas.1817567116

実験手法

X-RAY DIFFRACTION (1.75 Å)