2A4Z
Crystal Structure of human PI3Kgamma complexed with AS604850
Summary for 2A4Z
Entry DOI | 10.2210/pdb2a4z/pdb |
Related | 1e7u 1e7v 1e8w 1e8x 1e8y 2A5U |
Descriptor | 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) |
Functional Keywords | protein-inhibitor complex, pi3kg, transferase |
Biological source | Homo sapiens (human) |
Cellular location | Cytoplasm : P48736 |
Total number of polymer chains | 1 |
Total formula weight | 111041.39 |
Authors | 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. (deposition date: 2005-06-30, release date: 2005-09-20, Last modification date: 2023-10-25) |
Primary citation | 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 Cited by 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: 16127437DOI: 10.1038/nm1284 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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