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]

spinqualitylabelsall models 7lmp, resolution 2.29Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.29Å Ligands: NY6, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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 EC50 values, a 3000-fold enhancement over the screening hits. Crystal structures reveal a key pi-pi 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. Discovery of Potent Coumarin-Based Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains Using Structure-Based Design.,Yan NL, Santos-Martins D, Nair R, Chu A, Wilson IA, Johnson KA, Forli S, Morgan GJ, Petrassi HM, Kelly JW J Med Chem. 2021 May 13;64(9):6273-6299. doi: 10.1021/acs.jmedchem.1c00339. Epub , 2021 May 3. PMID:33939422 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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