2a5u: Difference between revisions
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==Crystal Structure of human PI3Kgamma complexed with AS605240== | |||
=== | <StructureSection load='2a5u' size='340' side='right' caption='[[2a5u]], [[Resolution|resolution]] 2.70Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2a5u]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A5U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2A5U FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=QYT:(5E)-5-(QUINOXALIN-6-YLMETHYLENE)-1,3-THIAZOLIDINE-2,4-DIONE'>QYT</scene><br> | |||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2a4z|2a4z]], [[1e7u|1e7u]], [[1e7v|1e7v]], [[1e7w|1e7w]], [[1e8x|1e8x]], [[1e8y|1e8y]]</td></tr> | |||
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2a5u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a5u OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2a5u RCSB], [http://www.ebi.ac.uk/pdbsum/2a5u PDBsum]</span></td></tr> | |||
<table> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/a5/2a5u_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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<ref>PMID:16127437</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Phosphoinositide 3-Kinases|Phosphoinositide 3-Kinases]] | *[[Phosphoinositide 3-Kinases|Phosphoinositide 3-Kinases]] | ||
== References == | |||
<references/> | |||
== | __TOC__ | ||
< | </StructureSection> | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]] | [[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]] | ||
Revision as of 07:21, 3 October 2014
Crystal Structure of human PI3Kgamma complexed with AS605240Crystal Structure of human PI3Kgamma complexed with AS605240
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedPhosphoinositide 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. 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Homo sapiens
- Phosphatidylinositol-4,5-bisphosphate 3-kinase
- 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.
- Pi3kg
- Protein-inhibitor complex
- Transferase