1orf

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[[Image:1orf.jpg|left|200px]]<br /><applet load="1orf" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1orf, resolution 2.40&Aring;" />
 
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'''The Oligomeric Structure of Human Granzyme A Reveals the Molecular Determinants of Substrate Specificity'''<br />
 
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==Overview==
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==The Oligomeric Structure of Human Granzyme A Reveals the Molecular Determinants of Substrate Specificity==
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The cell death-inducing serine protease granzyme A (GzmA) has a unique disulfide-linked quaternary structure. The structure of human GzmA bound to a tripeptide CMK inhibitor, determined at a resolution of 2.4 A, reveals that the oligomeric state contributes to substrate selection by limiting access to the active site for potential macromolecular substrates and inhibitors. Unlike other serine proteases, tetrapeptide substrate preferences do not correlate well with natural substrate cleavage sequences. This suggests that the context of the cleavage sequence within a macromolecular substrate imposes another level of selection not observed with the peptide substrates. Modeling of inhibitors bound to the GzmA active site shows that the dimer also contributes to substrate specificity in a unique manner by extending the active-site cleft. The crystal structure, along with substrate library profiling and mutagenesis, has allowed us to identify and rationally manipulate key components involved in GzmA substrate specificity.
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<StructureSection load='1orf' size='340' side='right'caption='[[1orf]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1orf]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ORF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1ORF 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]] 2.4&#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=0G6:D-PHENYLALANYL-N-[(2S,3S)-6-{[AMINO(IMINIO)METHYL]AMINO}-1-CHLORO-2-HYDROXYHEXAN-3-YL]-L-PROLINAMIDE'>0G6</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=1orf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1orf OCA], [https://pdbe.org/1orf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1orf RCSB], [https://www.ebi.ac.uk/pdbsum/1orf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1orf ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/GRAA_HUMAN GRAA_HUMAN] This enzyme is necessary for target cell lysis in cell-mediated immune responses. It cleaves after Lys or Arg. Cleaves APEX1 after 'Lys-31' and destroys its oxidative repair activity. Involved in apoptosis.<ref>PMID:12524539</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/or/1orf_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=1orf ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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1ORF 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=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Granzyme_A Granzyme A], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.78 3.4.21.78] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ORF OCA].
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*[[Granzyme|Granzyme]]
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== References ==
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==Reference==
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<references/>
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The oligomeric structure of human granzyme A is a determinant of its extended substrate specificity., Bell JK, Goetz DH, Mahrus S, Harris JL, Fletterick RJ, Craik CS, Nat Struct Biol. 2003 Jul;10(7):527-34. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12819769 12819769]
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__TOC__
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[[Category: Granzyme A]]
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Bell, J K.]]
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[[Category: Bell JK]]
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[[Category: Craik, C S.]]
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[[Category: Craik CS]]
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[[Category: Fletterick, R J.]]
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[[Category: Fletterick RJ]]
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[[Category: Goetz, D H.]]
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[[Category: Goetz DH]]
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[[Category: Harris, J L.]]
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[[Category: Harris JL]]
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[[Category: Mahrus, S.]]
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[[Category: Mahrus S]]
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[[Category: SO4]]
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[[Category: hydrolase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:20:45 2008''
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Current revision

The Oligomeric Structure of Human Granzyme A Reveals the Molecular Determinants of Substrate Specificity

PDB ID 1orf

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