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| | ==Crystal structure of human granzyme H with a peptidyl substrate== | | ==Crystal structure of human granzyme H with a peptidyl substrate== |
| - | <StructureSection load='3tjv' size='340' side='right' caption='[[3tjv]], [[Resolution|resolution]] 2.40Å' scene=''> | + | <StructureSection load='3tjv' size='340' side='right'caption='[[3tjv]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3tjv]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TJV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TJV FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3tjv]] 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=3TJV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TJV 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]] 2.4Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3tju|3tju]], [[3tk9|3tk9]]</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">GZMH, CGL2, CTSGL2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=3tjv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tjv OCA], [https://pdbe.org/3tjv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3tjv RCSB], [https://www.ebi.ac.uk/pdbsum/3tjv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3tjv 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=3tjv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tjv OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3tjv RCSB], [http://www.ebi.ac.uk/pdbsum/3tjv PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GRAH_HUMAN GRAH_HUMAN]] Cytotoxic chymotrypsin-like serine protease with preference for bulky and aromatic residues at the P1 position and acidic residues at the P3' and P4' sites. Probably necessary for target cell lysis in cell-mediated immune responses. Participates in the antiviral response via direct cleavage of several proteins essential for viral replication.<ref>PMID:22156497</ref> <ref>PMID:23269243</ref> | + | [https://www.uniprot.org/uniprot/GRAH_HUMAN GRAH_HUMAN] Cytotoxic chymotrypsin-like serine protease with preference for bulky and aromatic residues at the P1 position and acidic residues at the P3' and P4' sites. Probably necessary for target cell lysis in cell-mediated immune responses. Participates in the antiviral response via direct cleavage of several proteins essential for viral replication.<ref>PMID:22156497</ref> <ref>PMID:23269243</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 3tjv" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Fan, Z]] | + | [[Category: Large Structures]] |
| - | [[Category: Sun, F]] | + | [[Category: Fan Z]] |
| - | [[Category: Tong, L]] | + | [[Category: Sun F]] |
| - | [[Category: Wang, L]] | + | [[Category: Tong L]] |
| - | [[Category: Wu, L]] | + | [[Category: Wang L]] |
| - | [[Category: Zhang, K]] | + | [[Category: Wu L]] |
| - | [[Category: Cytolysis]]
| + | [[Category: Zhang K]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase substrate]]
| + | |
| - | [[Category: Serine protease]]
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| Structural highlights
Function
GRAH_HUMAN Cytotoxic chymotrypsin-like serine protease with preference for bulky and aromatic residues at the P1 position and acidic residues at the P3' and P4' sites. Probably necessary for target cell lysis in cell-mediated immune responses. Participates in the antiviral response via direct cleavage of several proteins essential for viral replication.[1] [2]
Publication Abstract from PubMed
Human granzyme H (GzmH) is constitutively expressed in human NK cells that have important roles in innate immune responses against tumors and viruses. GzmH is a chymotrypsin-like serine protease. Its substrate preference and its mechanism of substrate recognition are poorly understood. To provide structural insights into the substrate recognition mechanisms for GzmH, we solved the crystal structures of a D102N-GzmH mutant alone and in complex with a decapeptide substrate and an inhibitor to 2.2 A, 2.4 A, and 2.7 A, respectively. The Thr(189), Gly(216), and Gly(226) specificity triad in the S1 pocket of GzmH defines its preference for bulky, aromatic residues (Tyr and Phe) at the P1 position. Notably, we discovered that an unusual RKR motif (Arg(39)-Lys(40)-Arg(41)), conserved only in GzmH, helps define the S3' and S4' binding regions, indicating the preference for acidic residues at the P3' and P4' sites. Disruption of the RKR motif or the acidic P3' and P4' residues in the substrate abolished the proteolytic activity of GzmH. We designed a tetrapeptide chloromethylketone inhibitor, Ac-PTSY-chloromethylketone, which can selectively and efficiently block the enzymatic and cytotoxic activity of GzmH, providing a useful tool for further studies on the function of GzmH.
Structural Insights into the Substrate Specificity of Human Granzyme H: The Functional Roles of a Novel RKR Motif.,Wang L, Zhang K, Wu L, Liu S, Zhang H, Zhou Q, Tong L, Sun F, Fan Z J Immunol. 2011 Dec 9. PMID:22156497[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wang L, Zhang K, Wu L, Liu S, Zhang H, Zhou Q, Tong L, Sun F, Fan Z. Structural Insights into the Substrate Specificity of Human Granzyme H: The Functional Roles of a Novel RKR Motif. J Immunol. 2011 Dec 9. PMID:22156497 doi:10.4049/jimmunol.1101381
- ↑ Wang L, Li Q, Wu L, Liu S, Zhang Y, Yang X, Zhu P, Zhang H, Zhang K, Lou J, Liu P, Tong L, Sun F, Fan Z. Identification of SERPINB1 As a Physiological Inhibitor of Human Granzyme H. J Immunol. 2012 Dec 26. PMID:23269243 doi:10.4049/jimmunol.1202542
- ↑ Wang L, Zhang K, Wu L, Liu S, Zhang H, Zhou Q, Tong L, Sun F, Fan Z. Structural Insights into the Substrate Specificity of Human Granzyme H: The Functional Roles of a Novel RKR Motif. J Immunol. 2011 Dec 9. PMID:22156497 doi:10.4049/jimmunol.1101381
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