1i4e

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[[Image:1i4e.gif|left|200px]]<br /><applet load="1i4e" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1i4e, resolution 3.00&Aring;" />
 
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'''CRYSTAL STRUCTURE OF THE CASPASE-8/P35 COMPLEX'''<br />
 
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==Overview==
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==CRYSTAL STRUCTURE OF THE CASPASE-8/P35 COMPLEX==
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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.
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<StructureSection load='1i4e' size='340' side='right'caption='[[1i4e]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1i4e]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Autographa_californica_nucleopolyhedrovirus Autographa californica nucleopolyhedrovirus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1I4E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1I4E FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1i4e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1i4e OCA], [https://pdbe.org/1i4e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1i4e RCSB], [https://www.ebi.ac.uk/pdbsum/1i4e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1i4e ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/P35_NPVAC P35_NPVAC] Functions as an inhibitor of the host RNA interference antiviral response. Inhibits the insect host cell apoptotic response initiated by the viral infection. Blocks as well the activity of members of the caspase family of proteases. Required for late and very late gene expression.<ref>PMID:16081248</ref> <ref>PMID:1962198</ref> <ref>PMID:26018163</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/i4/1i4e_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1i4e ConSurf].
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<div style="clear:both"></div>
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==Disease==
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==See Also==
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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]]
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*[[Caspase 3D structures|Caspase 3D structures]]
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== References ==
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==About this Structure==
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<references/>
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1I4E is a [http://en.wikipedia.org/wiki/Protein_complex 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].
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__TOC__
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</StructureSection>
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==Reference==
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[[Category: Autographa californica nucleopolyhedrovirus]]
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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://ispc.weizmann.ac.il//pmbin/getpm?pmid=11260720 11260720]
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[[Category: Homo sapiens]]
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[[Category: Escherichia coli]]
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[[Category: Large Structures]]
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[[Category: Protein complex]]
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[[Category: Cirilli M]]
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[[Category: Cirilli, M.]]
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[[Category: Huang Y]]
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[[Category: Huang, Y.]]
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[[Category: Myszka DG]]
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[[Category: Myszka, D G.]]
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[[Category: Rich RL]]
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[[Category: Rich, R L.]]
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[[Category: Wu H]]
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[[Category: Wu, H.]]
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[[Category: Xu G]]
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[[Category: Xu, G.]]
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[[Category: covalent complex protease-inhibitor]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:07:55 2008''
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Current revision

CRYSTAL STRUCTURE OF THE CASPASE-8/P35 COMPLEX

PDB ID 1i4e

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