1shl
From Proteopedia
(New page: 200px<br /> <applet load="1shl" size="450" color="white" frame="true" align="right" spinBox="true" caption="1shl, resolution 3.00Å" /> '''CASPASE-7 IN COMPLE...) |
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| - | [[Image:1shl.gif|left|200px]]<br /> | + | [[Image:1shl.gif|left|200px]]<br /><applet load="1shl" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1shl" size=" | + | |
caption="1shl, resolution 3.00Å" /> | caption="1shl, resolution 3.00Å" /> | ||
'''CASPASE-7 IN COMPLEX WITH FICA ALLOSTERIC INHIBITOR'''<br /> | '''CASPASE-7 IN COMPLEX WITH FICA ALLOSTERIC INHIBITOR'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Allosteric regulation of proteins by conformational change is a primary | + | Allosteric regulation of proteins by conformational change is a primary means of biological control. Traditionally it has been difficult to identify and characterize novel allosteric sites and ligands that freeze these conformational states. We present a site-directed approach using Tethering for trapping inhibitory small molecules at sites away from the active site by reversible disulfide bond formation. We screened a library of 10,000 thiol-containing compounds against accessible cysteines of two members of the caspase family of proteases, caspase-3 and -7. We discovered a previously unreported and conserved allosteric site in a deep cavity at the dimer interface 14 A from the active site. This site contains a natural cysteine that, when disulfide-bonded with either of two specific compounds, inactivates these proteases. The allosteric site is functionally coupled to the active site, such that binding of the compounds at the allosteric site prevents peptide binding at the active site. The x-ray crystal structures of caspase-7 bound by either compound demonstrates that they inhibit caspase-7 by trapping a zymogen-like conformation. This approach may be useful to identify new allosteric sites from natural or engineered cysteines, to study allosteric transitions in proteins, and to nucleate drug discovery efforts. |
==About this Structure== | ==About this Structure== | ||
| - | 1SHL 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 FXN as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1SHL 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=FXN:'>FXN</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SHL OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Brien, T | + | [[Category: Brien, T O.]] |
| - | [[Category: Hardy, J | + | [[Category: Hardy, J A.]] |
[[Category: Lam, J.]] | [[Category: Lam, J.]] | ||
| - | [[Category: Nguyen, J | + | [[Category: Nguyen, J T.]] |
| - | [[Category: Wells, J | + | [[Category: Wells, J A.]] |
[[Category: FXN]] | [[Category: FXN]] | ||
[[Category: allosteric]] | [[Category: allosteric]] | ||
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[[Category: protease]] | [[Category: protease]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:01:33 2008'' |
Revision as of 13:01, 21 February 2008
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CASPASE-7 IN COMPLEX WITH FICA ALLOSTERIC INHIBITOR
Overview
Allosteric regulation of proteins by conformational change is a primary means of biological control. Traditionally it has been difficult to identify and characterize novel allosteric sites and ligands that freeze these conformational states. We present a site-directed approach using Tethering for trapping inhibitory small molecules at sites away from the active site by reversible disulfide bond formation. We screened a library of 10,000 thiol-containing compounds against accessible cysteines of two members of the caspase family of proteases, caspase-3 and -7. We discovered a previously unreported and conserved allosteric site in a deep cavity at the dimer interface 14 A from the active site. This site contains a natural cysteine that, when disulfide-bonded with either of two specific compounds, inactivates these proteases. The allosteric site is functionally coupled to the active site, such that binding of the compounds at the allosteric site prevents peptide binding at the active site. The x-ray crystal structures of caspase-7 bound by either compound demonstrates that they inhibit caspase-7 by trapping a zymogen-like conformation. This approach may be useful to identify new allosteric sites from natural or engineered cysteines, to study allosteric transitions in proteins, and to nucleate drug discovery efforts.
About this Structure
1SHL is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
Reference
Discovery of an allosteric site in the caspases., Hardy JA, Lam J, Nguyen JT, O'Brien T, Wells JA, Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12461-6. Epub 2004 Aug 16. PMID:15314233
Page seeded by OCA on Thu Feb 21 15:01:33 2008
Categories: Homo sapiens | Single protein | Brien, T O. | Hardy, J A. | Lam, J. | Nguyen, J T. | Wells, J A. | FXN | Allosteric | Caspase | Central-cavity | Cysteine protease | Dimer interface | Inhibitor | Protease
