Download MendeleyStabilization of amyloidogenic immunoglobulin light chains by small molecules.
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.(2019) Proc Natl Acad Sci U S A 116: 8360-8369
- PubMed: 30971495
- DOI: https://doi.org/10.1073/pnas.1817567116
- Primary Citation of Related Structures:
6MG4, 6MG5 - 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.
Organizational Affiliation:
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037; gjmorgan@bu.edu jkelly@scripps.edu.
