4MPV

Human beta-tryptase co-crystal structure with (2R,4S)-N,N'-bis[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]-4-hydroxy-2-(2-hydroxypropan-2-yl)-5,5-dimethyl-1,3-dioxolane-2,4-dicarboxamide

4MPV の概要

• エントリーDOI: 10.2210/pdb4mpv/pdb
• 関連するPDBエントリー: 4MPU 4MPW 4MPX 4MQA
• 分子名称: Tryptase alpha/beta-1, (2R,4S)-N,N'-bis[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]-4-hydroxy-2-(2-hydroxypropan-2-yl)-5,5-dimethyl-1,3-dioxolane-2,4-dicarboxamide, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: coferon, alpha-hydroxyketone, small molecule inhibitor, drug discovery, self-assembly, crystal catalysis, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 56640.04

構造登録者

White, A.,Stein, A.J.,Suto, R. (登録日: 2013-09-13, 公開日: 2015-03-18, 最終更新日: 2024-11-27)

主引用文献

Giardina, S.F.,Werner, D.S.,Pingle, M.,Foreman, K.W.,Bergstrom, D.E.,Arnold, L.D.,Barany, F.
Target-Directed Self-Assembly of Homodimeric Drugs Against beta-Tryptase.
Acs Med.Chem.Lett., 9:827-831, 2018

PubMed Abstract: Tryptase, a serine protease released from mast cells, is implicated in many allergic and inflammatory disorders. Human tryptase is a donut-shaped tetramer with the active sites facing inward forming a central pore. Bivalent ligands spanning two active sites potently inhibit this configuration, but these large compounds have poor drug-like properties. To overcome some of these challenges, we developed self-assembling molecules, called coferons, which deliver a larger compound in two parts. Using a pharmacophoric core and reversibly binding linkers to span two active sites, we have successfully produced three novel homodimeric tryptase inhibitors. Upon binding to tryptase, compounds reassembled into flexible homodimers, with significant improvements in IC (0.19 ± 0.08 μM) over controls (5.50 ± 0.09 μM), and demonstrate good activity in mast cell lines. These studies provide validation for this innovative technology that is especially well-suited for the delivery of dimeric drugs to modulate intracellular macromolecular targets.

PubMed: 30128075
DOI: 10.1021/acsmedchemlett.8b00204

実験手法

X-RAY DIFFRACTION (2.305 Å)