1i4e: Difference between revisions
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[[Image:1i4e.gif|left|200px]] | [[Image:1i4e.gif|left|200px]] | ||
'''CRYSTAL STRUCTURE OF THE CASPASE-8/P35 COMPLEX''' | {{Structure | ||
|PDB= 1i4e |SIZE=350|CAPTION= <scene name='initialview01'>1i4e</scene>, resolution 3.00Å | |||
|SITE= | |||
|LIGAND= | |||
|ACTIVITY= | |||
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}} | |||
'''CRYSTAL STRUCTURE OF THE CASPASE-8/P35 COMPLEX''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
1I4E is a [ | 1I4E is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1I4E OCA]. | ||
==Reference== | ==Reference== | ||
Covalent inhibition revealed by the crystal structure of the caspase-8/p35 complex., Xu G, Cirilli M, Huang Y, Rich RL, Myszka DG, Wu H, Nature. 2001 Mar 22;410(6827):494-7. PMID:[http:// | Covalent inhibition revealed by the crystal structure of the caspase-8/p35 complex., Xu G, Cirilli M, Huang Y, Rich RL, Myszka DG, Wu H, Nature. 2001 Mar 22;410(6827):494-7. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11260720 11260720] | ||
[[Category: Escherichia coli]] | [[Category: Escherichia coli]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
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[[Category: covalent complex protease-inhibitor]] | [[Category: covalent complex protease-inhibitor]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 11:45:23 2008'' | ||
Revision as of 12:45, 20 March 2008
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CRYSTAL STRUCTURE OF THE CASPASE-8/P35 COMPLEX
OverviewOverview
Apoptosis is a highly regulated process that is crucial for normal development and homeostasis of multicellular organisms. The p35 protein from baculoviruses effectively prevents apoptosis by its broad-spectrum caspase inhibition. Here we report the crystal structure of p35 in complex with human caspase-8 at 3.0 A resolution, and biochemical and mutagenesis studies based on the structural information. The structure reveals that the caspase is inhibited in the active site through a covalent thioester linkage to p35, which we confirmed by gel electrophoresis, hydroxylamine treatment and mass spectrometry experiments. The p35 protein undergoes dramatic conformational changes on cleavage by the caspase. The repositioning of the amino terminus of p35 into the active site of the caspase eliminates solvent accessibility of the catalytic dyad. This may be crucial for preventing hydrolysis of the thioester intermediate, which is supported by the abrogation of inhibitory activity through mutations at the N terminus of p35. The p35 protein also makes conserved contacts with the caspase outside the active-site region, providing the molecular basis for the broad-spectrum inhibitory activity of this protein. We demonstrate a new molecular mechanism of caspase inhibition, as well as protease inhibition in general.
DiseaseDisease
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 StructureAbout this Structure
1I4E is a Protein complex structure of sequences from Escherichia coli. Full crystallographic information is available from OCA.
ReferenceReference
Covalent inhibition revealed by the crystal structure of the caspase-8/p35 complex., Xu G, Cirilli M, Huang Y, Rich RL, Myszka DG, Wu H, Nature. 2001 Mar 22;410(6827):494-7. PMID:11260720
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