7LMP

Structure of full-length human lambda-6A light chain JTO in complex with stabilizer 36 [3-(2-(7-(diethylamino)-4-methyl-2-oxo-2H-chromen-3-yl)ethyl)-8-(1H-imidazole-4-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione]

Summary for 7LMP

• Entry DOI: 10.2210/pdb7lmp/pdb
• Descriptor: JTO light chain, PHOSPHATE ION, 3-[2-[7-(diethylamino)-4-methyl-2-oxidanylidene-chromen-3-yl]ethyl]-8-(1~{H}-imidazol-5-ylcarbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione, ... (4 entities in total)
• Functional Keywords: amyloidosis, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 47133.61

Authors

Yan, N.L.,Wilson, I.A.,Kelly, J.W. (deposition date: 2021-02-05, release date: 2021-05-19, Last modification date: 2024-11-20)

Primary citation

Yan, N.L.,Santos-Martins, D.,Nair, R.,Chu, A.,Wilson, I.A.,Johnson, K.A.,Forli, S.,Morgan, G.J.,Petrassi, H.M.,Kelly, J.W.
Discovery of Potent Coumarin-Based Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains Using Structure-Based Design.
J.Med.Chem., 64:6273-6299, 2021

PubMed Abstract: In immunoglobulin light-chain (LC) amyloidosis, transient unfolding or unfolding and proteolysis enable aggregation of LC proteins, causing potentially fatal organ damage. A drug that kinetically stabilizes LCs could suppress aggregation; however, LC sequences are variable and have no natural ligands, hindering drug development efforts. We previously identified high-throughput screening hits that bind to a site at the interface between the two variable domains of the LC homodimer. We hypothesized that extending the stabilizers beyond this initially characterized binding site would improve affinity. Here, using protease sensitivity assays, we identified stabilizers that can be divided into four substructures. Some stabilizers exhibit nanomolar EC values, a 3000-fold enhancement over the screening hits. Crystal structures reveal a key π-π stacking interaction with a conserved tyrosine residue that was not utilized by the screening hits. These data provide a foundation for developing LC stabilizers with improved binding selectivity and enhanced physicochemical properties.

PubMed: 33939422
DOI: 10.1021/acs.jmedchem.1c00339

Experimental method

X-RAY DIFFRACTION (2.29 Å)