1rwm
From Proteopedia
(New page: 200px<br /> <applet load="1rwm" size="450" color="white" frame="true" align="right" spinBox="true" caption="1rwm, resolution 2.70Å" /> '''Crystal structure o...) |
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| - | [[Image:1rwm.gif|left|200px]]<br /> | + | [[Image:1rwm.gif|left|200px]]<br /><applet load="1rwm" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1rwm" size=" | + | |
caption="1rwm, resolution 2.70Å" /> | caption="1rwm, resolution 2.70Å" /> | ||
'''Crystal structure of human caspase-1 in complex with 4-oxo-3-[2-(5-{[4-(quinoxalin-2-ylamino)-benzoylamino]-methyl}-thiophen-2-yl)-acetylamino]-pentanoic acid'''<br /> | '''Crystal structure of human caspase-1 in complex with 4-oxo-3-[2-(5-{[4-(quinoxalin-2-ylamino)-benzoylamino]-methyl}-thiophen-2-yl)-acetylamino]-pentanoic acid'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Caspase-1 is a key endopeptidase responsible for the post-translational | + | Caspase-1 is a key endopeptidase responsible for the post-translational processing of the IL-1beta and IL-18 cytokines and small-molecule inhibitors that modulate the activity of this enzyme are predicted to be important therapeutic treatments for many inflammatory diseases. A fragment-assembly approach, accompanied by structural analysis, was employed to generate caspase-1 inhibitors. With the aid of Tethering with extenders (small molecules that bind to the active-site cysteine and contain a free thiol), two novel fragments that bound to the active site and made a disulfide bond with the extender were identified by mass spectrometry. Direct linking of each fragment to the extender generated submicromolar reversible inhibitors that significantly reduced secretion of IL-1beta but not IL-6 from human peripheral blood mononuclear cells. Thus, Tethering with extenders facilitated rapid identification and synthesis of caspase-1 inhibitors with cell-based activity and subsequent structural analyses provided insights into the enzyme's ability to accommodate different inhibitor-binding modes in the active site. |
==About this Structure== | ==About this Structure== | ||
| - | 1RWM is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with Q2Y as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Caspase-1 Caspase-1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.36 3.4.22.36] Full crystallographic information is available from [http:// | + | 1RWM is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=Q2Y:'>Q2Y</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Caspase-1 Caspase-1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.36 3.4.22.36] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1RWM OCA]. |
==Reference== | ==Reference== | ||
| - | Structural analysis of caspase-1 inhibitors derived from Tethering., O'Brien T, Fahr BT, Sopko MM, Lam JW, Waal ND, Raimundo BC, Purkey HE, Pham P, Romanowski MJ, Acta | + | Structural analysis of caspase-1 inhibitors derived from Tethering., O'Brien T, Fahr BT, Sopko MM, Lam JW, Waal ND, Raimundo BC, Purkey HE, Pham P, Romanowski MJ, Acta Crystallogr Sect F Struct Biol Cryst Commun. 2005 May 1;61(Pt, 5):451-8. Epub 2005 Apr 9. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16511067 16511067] |
[[Category: Caspase-1]] | [[Category: Caspase-1]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Brien, T | + | [[Category: Brien, T O.]] |
| - | [[Category: Fahr, B | + | [[Category: Fahr, B T.]] |
| - | [[Category: Romanowski, M | + | [[Category: Romanowski, M J.]] |
| - | [[Category: Waal, N | + | [[Category: Waal, N D.]] |
[[Category: Q2Y]] | [[Category: Q2Y]] | ||
[[Category: protein-small molecule inhibitor complex]] | [[Category: protein-small molecule inhibitor complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:55:23 2008'' |
Revision as of 12:55, 21 February 2008
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Crystal structure of human caspase-1 in complex with 4-oxo-3-[2-(5-{[4-(quinoxalin-2-ylamino)-benzoylamino]-methyl}-thiophen-2-yl)-acetylamino]-pentanoic acid
Overview
Caspase-1 is a key endopeptidase responsible for the post-translational processing of the IL-1beta and IL-18 cytokines and small-molecule inhibitors that modulate the activity of this enzyme are predicted to be important therapeutic treatments for many inflammatory diseases. A fragment-assembly approach, accompanied by structural analysis, was employed to generate caspase-1 inhibitors. With the aid of Tethering with extenders (small molecules that bind to the active-site cysteine and contain a free thiol), two novel fragments that bound to the active site and made a disulfide bond with the extender were identified by mass spectrometry. Direct linking of each fragment to the extender generated submicromolar reversible inhibitors that significantly reduced secretion of IL-1beta but not IL-6 from human peripheral blood mononuclear cells. Thus, Tethering with extenders facilitated rapid identification and synthesis of caspase-1 inhibitors with cell-based activity and subsequent structural analyses provided insights into the enzyme's ability to accommodate different inhibitor-binding modes in the active site.
About this Structure
1RWM is a Protein complex structure of sequences from Homo sapiens with as ligand. Active as Caspase-1, with EC number 3.4.22.36 Full crystallographic information is available from OCA.
Reference
Structural analysis of caspase-1 inhibitors derived from Tethering., O'Brien T, Fahr BT, Sopko MM, Lam JW, Waal ND, Raimundo BC, Purkey HE, Pham P, Romanowski MJ, Acta Crystallogr Sect F Struct Biol Cryst Commun. 2005 May 1;61(Pt, 5):451-8. Epub 2005 Apr 9. PMID:16511067
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