1qtn
From Proteopedia
(New page: 200px<br /> <applet load="1qtn" size="450" color="white" frame="true" align="right" spinBox="true" caption="1qtn, resolution 1.20Å" /> '''CRYSTAL STRUCTURE O...) |
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| - | [[Image:1qtn.gif|left|200px]]<br /> | + | [[Image:1qtn.gif|left|200px]]<br /><applet load="1qtn" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="1qtn, resolution 1.20Å" /> | caption="1qtn, resolution 1.20Å" /> | ||
'''CRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-8 WITH THE TETRAPEPTIDE INHIBITOR ACE-IETD-ALDEHYDE'''<br /> | '''CRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-8 WITH THE TETRAPEPTIDE INHIBITOR ACE-IETD-ALDEHYDE'''<br /> | ||
==Overview== | ==Overview== | ||
| - | BACKGROUND: Caspases are a family of cysteine proteases that have | + | BACKGROUND: Caspases are a family of cysteine proteases that have important intracellular roles in inflammation and apoptosis. Caspase-8 activates downstream caspases which are unable to carry out autocatalytic processing and activation. Caspase-8 is designated as an initiator caspase and is believed to sit at the apex of the Fas- or TNF-mediated apoptotic cascade. In view of this role, the enzyme is an attractive target for the design of inhibitors aimed at blocking the undesirable cell death associated with a range of degenerative disorders. RESULTS: The structure of recombinant human caspase-8, covalently modified with the inhibitor acetyl-Ile-Glu-Thr-Asp-aldehyde, has been determined by X-ray crystallography to 1.2 A resolution. The asymmetric unit contains the p18-p11 heterodimer; the biologically important molecule contains two dimers. The overall fold is very similar to that of caspase-1 and caspase-3, but significant differences exist in the substrate-binding region. The structure answers questions about the enzyme-inhibitor complex that could not be explained from earlier caspase structures solved at lower resolution. CONCLUSIONS: The catalytic triad in caspase-8 comprises Cys360, His317 and the backbone carbonyl oxygen atom of Arg258, which points towards the Nepsilon atom of His317. The oxygen atom attached to the tetrahedral carbon in the thiohemiacetal group of the inhibitor is hydrogen bonded to Ndelta of His317, and is not in a region characteristic of a classical 'oxyanion hole'. The N-acetyl group of the inhibitor is in the trans configuration. The caspase-8-inhibitor structure provides the basis for understanding structure/function relationships in this important initiator of the proteolytic cascade that leads to programmed cell death. |
==Disease== | ==Disease== | ||
| - | Known diseases associated with this structure: Autoimmune lymphoproliferative syndrome, type IIB OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]], Breast cancer, protection against OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]], Hepatocellular carcinoma, somatic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]] | + | Known diseases associated with this structure: Autoimmune lymphoproliferative syndrome, type IIB OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]], Breast cancer, protection against OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]], Hepatocellular carcinoma, somatic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]], Lung cancer, protection against OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]] |
==About this Structure== | ==About this Structure== | ||
| - | 1QTN 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 ACE and DTD as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 1QTN 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=ACE:'>ACE</scene> and <scene name='pdbligand=DTD:'>DTD</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1QTN OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Watenpaugh, K | + | [[Category: Watenpaugh, K D.]] |
[[Category: Watt, W.]] | [[Category: Watt, W.]] | ||
[[Category: ACE]] | [[Category: ACE]] | ||
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[[Category: tetramer]] | [[Category: tetramer]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:43:33 2008'' |
Revision as of 12:43, 21 February 2008
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CRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-8 WITH THE TETRAPEPTIDE INHIBITOR ACE-IETD-ALDEHYDE
Contents |
Overview
BACKGROUND: Caspases are a family of cysteine proteases that have important intracellular roles in inflammation and apoptosis. Caspase-8 activates downstream caspases which are unable to carry out autocatalytic processing and activation. Caspase-8 is designated as an initiator caspase and is believed to sit at the apex of the Fas- or TNF-mediated apoptotic cascade. In view of this role, the enzyme is an attractive target for the design of inhibitors aimed at blocking the undesirable cell death associated with a range of degenerative disorders. RESULTS: The structure of recombinant human caspase-8, covalently modified with the inhibitor acetyl-Ile-Glu-Thr-Asp-aldehyde, has been determined by X-ray crystallography to 1.2 A resolution. The asymmetric unit contains the p18-p11 heterodimer; the biologically important molecule contains two dimers. The overall fold is very similar to that of caspase-1 and caspase-3, but significant differences exist in the substrate-binding region. The structure answers questions about the enzyme-inhibitor complex that could not be explained from earlier caspase structures solved at lower resolution. CONCLUSIONS: The catalytic triad in caspase-8 comprises Cys360, His317 and the backbone carbonyl oxygen atom of Arg258, which points towards the Nepsilon atom of His317. The oxygen atom attached to the tetrahedral carbon in the thiohemiacetal group of the inhibitor is hydrogen bonded to Ndelta of His317, and is not in a region characteristic of a classical 'oxyanion hole'. The N-acetyl group of the inhibitor is in the trans configuration. The caspase-8-inhibitor structure provides the basis for understanding structure/function relationships in this important initiator of the proteolytic cascade that leads to programmed cell death.
Disease
Known diseases associated with this structure: Autoimmune lymphoproliferative syndrome, type IIB OMIM:[601763], Breast cancer, protection against OMIM:[601763], Hepatocellular carcinoma, somatic OMIM:[601763], Lung cancer, protection against OMIM:[601763]
About this Structure
1QTN is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
Reference
The atomic-resolution structure of human caspase-8, a key activator of apoptosis., Watt W, Koeplinger KA, Mildner AM, Heinrikson RL, Tomasselli AG, Watenpaugh KD, Structure. 1999 Sep 15;7(9):1135-43. PMID:10508785
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