7LMN

Structure of full-length human lambda-6A light chain JTO in complex with stabilizer 26 [2-(7-(diethylamino)-4-methyl-2-oxo-2H-chromen-3-yl)ethyl (3-(1H-imidazol-4-yl)benzyl)carbamate]

7LMN の概要

• エントリーDOI: 10.2210/pdb7lmn/pdb
• 分子名称: JTO light chain, 2-[7-(diethylamino)-4-methyl-2-oxidanylidene-chromen-3-yl]ethyl ~{N}-[[3-(1~{H}-imidazol-5-yl)phenyl]methyl]carbamate, PHOSPHATE ION, ... (4 entities in total)
• 機能のキーワード: amyloidosis, immune system
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 47087.58

構造登録者

Yan, N.L.,Wilson, I.A.,Kelly, J.W. (登録日: 2021-02-05, 公開日: 2021-05-19, 最終更新日: 2024-10-30)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.01 Å)