7RTP

Structure of full-length human lambda-6A light chain JTO in complex with urea stabilizer 20 [1-(2-(7-(diethylamino)-4-methyl-2-oxo-2H-chromen-3-yl)ethyl)-3-(pyridin-3-ylmethyl)urea]

Summary for 7RTP

• Entry DOI: 10.2210/pdb7rtp/pdb
• Descriptor: JTO light chain, PHOSPHATE ION, N-{2-[7-(diethylamino)-4-methyl-2-oxo-2H-1-benzopyran-3-yl]ethyl}-N'-[(pyridin-3-yl)methyl]urea, ... (4 entities in total)
• Functional Keywords: amyloidosis, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 47021.52

Authors

Yan, N.L.,Wilson, I.A.,Kelly, J.W. (deposition date: 2021-08-13, release date: 2022-02-16, Last modification date: 2024-10-30)

Primary citation

Yan, N.L.,Nair, R.,Chu, A.,Wilson, I.A.,Johnson, K.A.,Morgan, G.J.,Kelly, J.W.
Amyloidogenic immunoglobulin light chain kinetic stabilizers comprising a simple urea linker module reveal a novel binding sub-site.
Bioorg.Med.Chem.Lett., 60:128571-128571, 2022

PubMed Abstract: In immunoglobulin light chain (LC) amyloidosis, the misfolding, or misfolding and misassembly of LC a protein or fragments thereof resulting from aberrant endoproteolysis, causes organ damage to patients. A small molecule "kinetic stabilizer" drug could slow or stop these processes and improve prognosis. We previously identified coumarin-based kinetic stabilizers of LCs that can be divided into four components, including a "linker module" and "distal substructure". Our prior studies focused on characterizing carbamate, hydantoin, and spirocyclic urea linker modules, which bind in a solvent-exposed site at the V-V domain interface of the LC dimer. Here, we report structure-activity relationship data on 7-diethylamino coumarin-based kinetic stabilizers. This substructure occupies the previously characterized "anchor cavity" and the "aromatic slit". The potencies of amide and urea linker modules terminating in a variety of distal substructures attached at the 3-position of this coumarin ring were assessed. Surprisingly, crystallographic data on a 7-diethylamino coumarin-based kinetic stabilizer reveals that the urea linker module and distal substructure attached at the 3-position bind a solvent-exposed region of the full-length LC dimer distinct from previously characterized sites. Our results further elaborate the small-molecule binding surface of LCs that could be occupied by potent and selective LC kinetic stabilizers.

PubMed: 35065233
DOI: 10.1016/j.bmcl.2022.128571

Experimental method

X-RAY DIFFRACTION (2.09 Å)