6MG5
Structure of full-length human lambda-6A light chain JTO in complex with coumarin 1
Summary for 6MG5
| Entry DOI | 10.2210/pdb6mg5/pdb |
| Descriptor | Light chain JTO, PHOSPHATE ION, 7-(diethylamino)-4-methyl-2H-1-benzopyran-2-one, ... (4 entities in total) |
| Functional Keywords | light chain, amyloidosis, immune system |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 47280.87 |
| Authors | Morgan, G.J.,Yan, N.L.,Mortenson, D.E.,Stanfield, R.L.,Wilson, I.A.,Kelly, J.W. (deposition date: 2018-09-12, release date: 2019-04-10, Last modification date: 2024-11-06) |
| Primary citation | 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 Cited by 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: 30971495DOI: 10.1073/pnas.1817567116 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
Download full validation report
