2A4Z

Crystal Structure of human PI3Kgamma complexed with AS604850

2A4Z の概要

• エントリーDOI: 10.2210/pdb2a4z/pdb
• 関連するPDBエントリー: 1e7u 1e7v 1e8w 1e8x 1e8y 2A5U
• 分子名称: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, gamma isoform, (5E)-5-[(2,2-DIFLUORO-1,3-BENZODIOXOL-5-YL)METHYLENE]-1,3-THIAZOLIDINE-2,4-DIONE (3 entities in total)
• 機能のキーワード: protein-inhibitor complex, pi3kg, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm : P48736
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 111041.39

構造登録者

Camps, M.,Ruckle, T.,Ji, H.,Ardissone, V.,Rintelen, F.,Shaw, J.,Ferrandi, C.,Chabert, C.,Gillieron, C.,Francon, B.,Martin, T.,Gretener, D.,Perrin, D.,Leroy, D.,Vitte, P.-A.,Hirsch, E.,Wymann, M.P.,Cirillo, R.,Schwarz, M.K.,Rommel, C. (登録日: 2005-06-30, 公開日: 2005-09-20, 最終更新日: 2023-10-25)

主引用文献

Camps, M.,Ruckle, T.,Ji, H.,Ardissone, V.,Rintelen, F.,Shaw, J.,Ferrandi, C.,Chabert, C.,Gillieron, C.,Francon, B.,Martin, T.,Gretener, D.,Perrin, D.,Leroy, D.,Vitte, P.-A.,Hirsch, E.,Wymann, M.P.,Cirillo, R.,Schwarz, M.K.,Rommel, C.
Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis
NAT.MED. (N.Y.), 11:936-943, 2005

PubMed Abstract: Phosphoinositide 3-kinases (PI3K) have long been considered promising drug targets for the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. But the lack of specificity, isoform selectivity and poor biopharmaceutical profile of PI3K inhibitors have so far hampered rigorous disease-relevant target validation. Here we describe the identification and development of specific, selective and orally active small-molecule inhibitors of PI3Kgamma (encoded by Pik3cg). We show that Pik3cg(-/-) mice are largely protected in mouse models of rheumatoid arthritis; this protection correlates with defective neutrophil migration, further validating PI3Kgamma as a therapeutic target. We also describe that oral treatment with a PI3Kgamma inhibitor suppresses the progression of joint inflammation and damage in two distinct mouse models of rheumatoid arthritis, reproducing the protective effects shown by Pik3cg(-/-) mice. Our results identify selective PI3Kgamma inhibitors as potential therapeutic molecules for the treatment of chronic inflammatory disorders such as rheumatoid arthritis.

PubMed: 16127437
DOI: 10.1038/nm1284

実験手法

X-RAY DIFFRACTION (2.9 Å)