4AFQ

Human Chymase - Fynomer Complex

4AFQ の概要

• エントリーDOI: 10.2210/pdb4afq/pdb
• 関連するPDBエントリー: 1A0N 1AOT 1AOU 1AVZ 1AZG 1EFN 1FYN 1G83 1KLT 1M27 1NN6 1NYF 1NYG 1PJP 1SHF 1T31 1ZBJ 2DQ7 4AFS 4AFU 4AFZ
• 分子名称: CHYMASE, FYNOMER, CITRATE ANION, ... (5 entities in total)
• 機能のキーワード: hydrolase-de novo protein complex, inhibitor, serine protease, hydrolase/de novo protein
• 由来する生物種: HOMO SAPIENS; 詳細
• 細胞内の位置: Secreted: P23946
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 70407.22

構造登録者

Schlatter, D.,Brack, S.,Banner, D.W.,Batey, S.,Benz, J.,Bertschinger, J.,Huber, W.,Joseph, C.,Rufer, A.,Van Der Kloosters, A.,Weber, M.,Grabulovski, D.,Hennig, M. (登録日: 2012-01-23, 公開日: 2012-07-11, 最終更新日: 2024-05-01)

主引用文献

Schlatter, D.,Brack, S.,Banner, D.W.,Batey, S.,Benz, J.,Bertschinger, J.,Huber, W.,Joseph, C.,Rufer, A.,Van Der Klooster, A.,Weber, M.,Grabulovski, D.,Hennig, M.
Generation, Characterization and Structural Data of Chymase Binding Proteins Based on the Human Fyn Kinase SH3 Domain.
Mabs, 4:497-, 2012

PubMed Abstract: The serine protease chymase (EC = 3.4.21.39) is expressed in the secretory granules of mast cells, which are important in allergic reactions. Fynomers, which are binding proteins derived from the Fyn SH3 domain, were generated against human chymase to produce binding partners to facilitate crystallization, structure determination and structure-based drug discovery, and to provide inhibitors of chymase for therapeutic applications. The best Fynomer was found to bind chymase with a KD of 0.9 nM and koff of 6.6x10 (-4) s (-1) , and to selectively inhibit chymase activity with an IC 50 value of 2 nM. Three different Fynomers were co-crystallized with chymase in 6 different crystal forms overall, with diffraction quality in the range of 2.25 to 1.4 Å resolution, which is suitable for drug design efforts. The X-ray structures show that all Fynomers bind to the active site of chymase. The conserved residues Arg15-Trp16-Thr17 in the RT-loop of the chymase binding Fynomers provide a tight interaction, with Trp16 pointing deep into the S1 pocket of chymase. These results confirm the suitability of Fynomers as research tools to facilitate protein crystallization, as well as for the development of assays to investigate the biological mechanism of targets. Finally, their highly specific inhibitory activity and favorable molecular properties support the use of Fynomers as potential therapeutic agents.

PubMed: 22653218
DOI: 10.4161/MABS.20452

実験手法

X-RAY DIFFRACTION (1.51 Å)