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| | ==Crystal Structure of D86N-GzmM Complexed with Its Optimal Synthesized Substrate== | | ==Crystal Structure of D86N-GzmM Complexed with Its Optimal Synthesized Substrate== |
| - | <StructureSection load='2zgj' size='340' side='right' caption='[[2zgj]], [[Resolution|resolution]] 2.30Å' scene=''> | + | <StructureSection load='2zgj' size='340' side='right'caption='[[2zgj]], [[Resolution|resolution]] 2.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2zgj]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ZGJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ZGJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2zgj]] is a 2 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=2ZGJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ZGJ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2zgc|2zgc]], [[2zgh|2zgh]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GZMM, MET1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2zgj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2zgj OCA], [https://pdbe.org/2zgj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2zgj RCSB], [https://www.ebi.ac.uk/pdbsum/2zgj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2zgj ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2zgj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2zgj OCA], [http://pdbe.org/2zgj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2zgj RCSB], [http://www.ebi.ac.uk/pdbsum/2zgj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2zgj ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GRAM_HUMAN GRAM_HUMAN]] Cleaves peptide substrates after methionine, leucine, and norleucine. Physiological substrates include EZR, alpha-tubulins and the apoptosis inhibitor BIRC5/Survivin. Promotes caspase activation and subsequent apoptosis of target cells.<ref>PMID:18523284</ref> <ref>PMID:20406824</ref> | + | [https://www.uniprot.org/uniprot/GRAM_HUMAN GRAM_HUMAN] Cleaves peptide substrates after methionine, leucine, and norleucine. Physiological substrates include EZR, alpha-tubulins and the apoptosis inhibitor BIRC5/Survivin. Promotes caspase activation and subsequent apoptosis of target cells.<ref>PMID:18523284</ref> <ref>PMID:20406824</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | <jmolCheckbox> | | <jmolCheckbox> |
| | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/zg/2zgj_consurf.spt"</scriptWhenChecked> | | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/zg/2zgj_consurf.spt"</scriptWhenChecked> |
| - | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Fan, Z S]] | + | [[Category: Large Structures]] |
| - | [[Category: Hua, G Q]] | + | [[Category: Fan ZS]] |
| - | [[Category: Liu, K]] | + | [[Category: Hua GQ]] |
| - | [[Category: Sun, F]] | + | [[Category: Liu K]] |
| - | [[Category: Wang, L]] | + | [[Category: Sun F]] |
| - | [[Category: Wu, L F]] | + | [[Category: Wang L]] |
| - | [[Category: Zhai, Y J]] | + | [[Category: Wu LF]] |
| - | [[Category: Cytolysis]]
| + | [[Category: Zhai YJ]] |
| - | [[Category: Glycoprotein]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Secreted]]
| + | |
| - | [[Category: Serine protease]]
| + | |
| - | [[Category: Synthesized peptide]]
| + | |
| - | [[Category: Zymogen]]
| + | |
| Structural highlights
Function
GRAM_HUMAN Cleaves peptide substrates after methionine, leucine, and norleucine. Physiological substrates include EZR, alpha-tubulins and the apoptosis inhibitor BIRC5/Survivin. Promotes caspase activation and subsequent apoptosis of target cells.[1] [2]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Granzyme M (GzmM), a unique serine protease constitutively expressed in NK cells, is important for granule-mediated cytolysis and can induce rapid caspase-dependent apoptosis of tumor cells. However, few substrates of GzmM have been reported to date, and the mechanism by which this enzyme recognizes and hydrolyzes substrates is unknown. To provide structural insights into the proteolytic specificity of human GzmM (hGzmM), crystal structures of wild-type hGzmM, the inactive D86N-GzmM mutant with bound peptide substrate, and the complexes with a catalytic product and with a tetrapeptide chloromethylketone inhibitor were solved to 1.96 A, 2.30 A, 2.17 A and 2.70 A, respectively. Structure-based mutagenesis revealed that the N terminus and catalytic triad of hGzmM are most essential for proteolytic function. In particular, D86N-GzmM was found to be an ideal inactive enzyme for functional studies. Structural comparisons indicated a large conformational change of the L3 loop upon substrate binding, and suggest this loop mediates the substrate specificity of hGzmM. Based on the complex structure of GzmM with its catalytic product, a tetrapeptide chloromethylketone inhibitor was designed and found to specifically block the catalytic activity of hGzmM.
Structural basis for proteolytic specificity of the human apoptosis-inducing granzyme M.,Wu L, Wang L, Hua G, Liu K, Yang X, Zhai Y, Bartlam M, Sun F, Fan Z J Immunol. 2009 Jul 1;183(1):421-9. PMID:19542453[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Bovenschen N, de Koning PJ, Quadir R, Broekhuizen R, Damen JM, Froelich CJ, Slijper M, Kummer JA. NK cell protease granzyme M targets alpha-tubulin and disorganizes the microtubule network. J Immunol. 2008 Jun 15;180(12):8184-91. PMID:18523284
- ↑ Hu D, Liu S, Shi L, Li C, Wu L, Fan Z. Cleavage of survivin by Granzyme M triggers degradation of the survivin-X-linked inhibitor of apoptosis protein (XIAP) complex to free caspase activity leading to cytolysis of target tumor cells. J Biol Chem. 2010 Jun 11;285(24):18326-35. doi: 10.1074/jbc.M109.083170. Epub, 2010 Apr 20. PMID:20406824 doi:http://dx.doi.org/10.1074/jbc.M109.083170
- ↑ Wu L, Wang L, Hua G, Liu K, Yang X, Zhai Y, Bartlam M, Sun F, Fan Z. Structural basis for proteolytic specificity of the human apoptosis-inducing granzyme M. J Immunol. 2009 Jul 1;183(1):421-9. PMID:19542453 doi:183/1/421
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