1qdu
From Proteopedia
(New page: 200px<br /> <applet load="1qdu" size="450" color="white" frame="true" align="right" spinBox="true" caption="1qdu, resolution 2.8Å" /> '''CRYSTAL STRUCTURE OF...) |
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| - | [[Image:1qdu.gif|left|200px]]<br /> | + | [[Image:1qdu.gif|left|200px]]<br /><applet load="1qdu" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="1qdu, resolution 2.8Å" /> | caption="1qdu, resolution 2.8Å" /> | ||
'''CRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-8 WITH THE TRIPEPTIDE KETONE INHIBITOR ZEVD-DCBMK'''<br /> | '''CRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-8 WITH THE TRIPEPTIDE KETONE INHIBITOR ZEVD-DCBMK'''<br /> | ||
==Overview== | ==Overview== | ||
| - | BACKGROUND: In the initial stages of Fas-mediated apoptosis the cysteine | + | BACKGROUND: In the initial stages of Fas-mediated apoptosis the cysteine protease caspase-8 is recruited to the cell receptor as a zymogen (procaspase-8) and is incorporated into the death-signalling complex. Procaspase-8 is subsequently activated leading to a cascade of proteolytic events, one of them being the activation of caspase-3, and ultimately resulting in cell destruction. Variations in the substrate specificity of different caspases have been reported. RESULTS: We report here the crystal structure of a complex of the activated human caspase-8 (proteolytic domain) with the irreversible peptidic inhibitor Z-Glu-Val-Asp-dichloromethylketone at 2.8 A resolution. This is the first structure of a representative of the long prodomain initiator caspases and of the group III substrate specificity class. The overall protein architecture resembles the caspase-1 and caspase-3 folds, but shows distinct structural differences in regions forming the active site. In particular, differences observed in subsites S(3), S(4) and the loops involved in inhibitor interactions explain the preference of caspase-8 for substrates with the sequence (Leu/Val)-Glu-X-Asp. CONCLUSIONS: The structural differences could be correlated with the observed substrate specificities of caspase-1, caspase-3 and caspase-8, as determined from kinetic experiments. This information will help us to understand the role of the various caspases in the propagation of the apoptotic signal. The information gained from this investigation should be useful for the design of specific inhibitors. |
==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== | ||
| - | 1QDU 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 PHQ as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1QDU 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=PHQ:'>PHQ</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1QDU OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Blanchard, H.]] | [[Category: Blanchard, H.]] | ||
| - | [[Category: Grutter, M | + | [[Category: Grutter, M G.]] |
[[Category: PHQ]] | [[Category: PHQ]] | ||
[[Category: complex (protease/inhibitor) apoptosis]] | [[Category: complex (protease/inhibitor) apoptosis]] | ||
[[Category: cysteine-protease]] | [[Category: cysteine-protease]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:38:36 2008'' |
Revision as of 12:38, 21 February 2008
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CRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-8 WITH THE TRIPEPTIDE KETONE INHIBITOR ZEVD-DCBMK
Contents |
Overview
BACKGROUND: In the initial stages of Fas-mediated apoptosis the cysteine protease caspase-8 is recruited to the cell receptor as a zymogen (procaspase-8) and is incorporated into the death-signalling complex. Procaspase-8 is subsequently activated leading to a cascade of proteolytic events, one of them being the activation of caspase-3, and ultimately resulting in cell destruction. Variations in the substrate specificity of different caspases have been reported. RESULTS: We report here the crystal structure of a complex of the activated human caspase-8 (proteolytic domain) with the irreversible peptidic inhibitor Z-Glu-Val-Asp-dichloromethylketone at 2.8 A resolution. This is the first structure of a representative of the long prodomain initiator caspases and of the group III substrate specificity class. The overall protein architecture resembles the caspase-1 and caspase-3 folds, but shows distinct structural differences in regions forming the active site. In particular, differences observed in subsites S(3), S(4) and the loops involved in inhibitor interactions explain the preference of caspase-8 for substrates with the sequence (Leu/Val)-Glu-X-Asp. CONCLUSIONS: The structural differences could be correlated with the observed substrate specificities of caspase-1, caspase-3 and caspase-8, as determined from kinetic experiments. This information will help us to understand the role of the various caspases in the propagation of the apoptotic signal. The information gained from this investigation should be useful for the design of specific inhibitors.
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
1QDU is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
Reference
The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis., Blanchard H, Kodandapani L, Mittl PR, Marco SD, Krebs JF, Wu JC, Tomaselli KJ, Grutter MG, Structure. 1999 Sep 15;7(9):1125-33. PMID:10508784
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