2a5u
From Proteopedia
(New page: 200px<br /> <applet load="2a5u" size="450" color="white" frame="true" align="right" spinBox="true" caption="2a5u, resolution 2.700Å" /> '''Crystal Structure ...) |
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| - | [[Image:2a5u.gif|left|200px]]<br /> | + | [[Image:2a5u.gif|left|200px]]<br /><applet load="2a5u" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2a5u" size=" | + | |
caption="2a5u, resolution 2.700Å" /> | caption="2a5u, resolution 2.700Å" /> | ||
'''Crystal Structure of human PI3Kgamma complexed with AS605240'''<br /> | '''Crystal Structure of human PI3Kgamma complexed with AS605240'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Phosphoinositide 3-kinases (PI3K) have long been considered promising drug | + | 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. |
==About this Structure== | ==About this Structure== | ||
| - | 2A5U is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with QYT as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] Full crystallographic information is available from [http:// | + | 2A5U is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=QYT:'>QYT</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A5U OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Rommel, C.]] | [[Category: Rommel, C.]] | ||
[[Category: Ruckle, T.]] | [[Category: Ruckle, T.]] | ||
| - | [[Category: Schwarz, M | + | [[Category: Schwarz, M K.]] |
[[Category: Shaw, J.]] | [[Category: Shaw, J.]] | ||
| - | [[Category: Vitte, P | + | [[Category: Vitte, P A.]] |
| - | [[Category: Wymann, M | + | [[Category: Wymann, M P.]] |
[[Category: QYT]] | [[Category: QYT]] | ||
[[Category: pi3kg]] | [[Category: pi3kg]] | ||
[[Category: protein-inhibitor complex]] | [[Category: protein-inhibitor complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:23:52 2008'' |
Revision as of 14:23, 21 February 2008
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Crystal Structure of human PI3Kgamma complexed with AS605240
Overview
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.
About this Structure
2A5U is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Phosphatidylinositol-4,5-bisphosphate 3-kinase, with EC number 2.7.1.153 Full crystallographic information is available from OCA.
Reference
Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis., 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 PA, Hirsch E, Wymann MP, Cirillo R, Schwarz MK, Rommel C, Nat Med. 2005 Sep;11(9):936-43. Epub 2005 Aug 28. PMID:16127437
Page seeded by OCA on Thu Feb 21 16:23:52 2008
Categories: Homo sapiens | Phosphatidylinositol-4,5-bisphosphate 3-kinase | Single protein | Ardissone, V. | Camps, M. | Chabert, C. | Cirillo, R. | Ferrandi, C. | Francon, B. | Gillieron, C. | Gretener, D. | Hirsch, E. | Ji, H. | Leroy, D. | Martin, T. | Perrin, D. | Rintelen, F. | Rommel, C. | Ruckle, T. | Schwarz, M K. | Shaw, J. | Vitte, P A. | Wymann, M P. | QYT | Pi3kg | Protein-inhibitor complex
