4XG9

Crystal structure of an inhibitor-bound Syk

4XG9 の概要

• エントリーDOI: 10.2210/pdb4xg9/pdb
• 関連するPDBエントリー: 4XG2 4XG3 4XG4 4XG5 4XG6 4XG7 4XG8
• 分子名称: Tyrosine-protein kinase SYK, 1-[(1-{2-[(3-chloro-1,2-dimethyl-1H-indol-5-yl)amino]pyrimidin-4-yl}-3-methyl-1H-pyrazol-4-yl)methyl]azetidin-3-ol (3 entities in total)
• 機能のキーワード: syk kinase, inhibitor, spleen tyrosine kinase, transferase-transferase inhibitor complex, transferase/transferase 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: 68677.78

構造登録者

Lee, S.J.,Choi, J.,Han, B.G.,Song, H.,Koh, J.S.,Lee, B.I. (登録日: 2014-12-30, 公開日: 2015-12-30, 最終更新日: 2023-11-08)

主引用文献

Lee, S.J.,Choi, J.S.,Han, B.G.,Kim, H.S.,Song, H.J.,Lee, J.,Nam, S.,Goh, S.H.,Kim, J.H.,Koh, J.S.,Lee, B.I.
Crystal structures of spleen tyrosine kinase in complex with novel inhibitors: structural insights for design of anticancer drugs
Febs J., 283:3613-3625, 2016

PubMed Abstract: Spleen tyrosine kinase (SYK) is a cytosolic nonreceptor protein tyrosine kinase that mediates key signal transduction pathways following the activation of immune cell receptors. SYK regulates cellular events induced by the B-cell receptor and Fc receptors with high intrinsic activity. Furthermore, SYK has been regarded as an attractive target for the treatment of autoimmune diseases and cancers. Here, we report the crystal structures of SYK in complex with seven newly developed inhibitors (G206, G207, O178, O194, O259, O272, and O282) to provide structural insights into which substituents of the inhibitors and binding regions of SYK are essential for lead compound optimization. Our kinase inhibitors exhibited high inhibitory activities against SYK, with half-maximal inhibitory concentrations (IC ) of approximately 0.7-33 nm, but they showed dissimilar inhibitory activities against KDR, RET, JAK2, JAK3, and FLT3. Among the seven SYK inhibitors, O272 and O282 exhibited highly specific inhibitions against SYK, whereas O194 exhibited strong inhibition of both SYK and FLT3. Three inhibitors (G206, G207, and O178) more efficiently inhibited FLT3 while still substantially inhibiting SYK activity. The binding mode analysis suggested that a highly selective SYK inhibitor can be developed by optimizing the functional groups that facilitate direct interactions with Asn499.

PubMed: 27504936
DOI: 10.1111/febs.13831

実験手法

X-RAY DIFFRACTION (2.91 Å)