3TUB

Crystal structure of SYK kinase domain with 1-(5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-yl)-3-((1R,2S)-2-phenylcyclopropyl)urea

3TUB の概要

• エントリーDOI: 10.2210/pdb3tub/pdb
• 関連するPDBエントリー: 3TUC 3TUD
• 分子名称: Tyrosine-protein kinase SYK, 1-{5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-yl}-3-[(1R,2S)-2-phenylcyclopropyl]urea (3 entities in total)
• 機能のキーワード: kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cell membrane (Probable): P43405
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34508.60

構造登録者

Han, S. (登録日: 2011-09-16, 公開日: 2012-08-29, 最終更新日: 2024-02-28)

主引用文献

Lovering, F.,McDonald, J.,Whitlock, G.A.,Glossop, P.A.,Phillips, C.,Bent, A.,Sabnis, Y.,Ryan, M.,Fitz, L.,Lee, J.,Chang, J.S.,Han, S.,Kurumbail, R.,Thorarensen, A.
Identification of Type-II Inhibitors Using Kinase Structures.
Chem.Biol.Drug Des., 80:657-664, 2012

PubMed Abstract: Spleen tyrosine kinase is a non-receptor tyrosine kinase, overactivation of which is thought to contribute to autoimmune diseases as well as allergy and asthma. Protein kinases have a highly conserved ATP binding site, thus making challenging the design of selective small molecule inhibitors. It has been well documented that some protein kinases can be stabilized in their inactive conformations (Type-II inhibitors). Herein, we describe a protein structure/ligand-based approach to successfully identify ligands that bind to novel conformations of spleen tyrosine kinase. By utilizing kinase protein crystal structures both in the public domain (RCSB) and within Pfizer's protein crystal database, we report the discovery of the first spleen tyrosine kinase Type-II ligands. Compounds 1 and 3 were found to bind to the DFG-out conformation of spleen tyrosine kinase, while compound 2 binds to a DFG-in, C-Helix-out conformation. In this instance, the C-helix moved significantly to create a large hydrophobic pocket rarely seen in kinase protein crystal structures.

PubMed: 22759374
DOI: 10.1111/j.1747-0285.2012.01443.x

実験手法

X-RAY DIFFRACTION (2.23 Å)