3tk9: Difference between revisions
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==Crystal structure of human granzyme H== | |||
=== | <StructureSection load='3tk9' size='340' side='right' caption='[[3tk9]], [[Resolution|resolution]] 2.20Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3tk9]] is a 1 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=3TK9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TK9 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> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3tju|3tju]], [[3tjv|3tjv]]</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3tk9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tk9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3tk9 RCSB], [http://www.ebi.ac.uk/pdbsum/3tk9 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:22156497</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Granzyme|Granzyme]] | *[[Granzyme|Granzyme]] | ||
== References == | |||
== | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Fan, Z | [[Category: Fan, Z]] | ||
[[Category: Sun, F | [[Category: Sun, F]] | ||
[[Category: Tong, L | [[Category: Tong, L]] | ||
[[Category: Wang, L | [[Category: Wang, L]] | ||
[[Category: Wu, L | [[Category: Wu, L]] | ||
[[Category: Zhang, K | [[Category: Zhang, K]] | ||
[[Category: Cytolysis]] | [[Category: Cytolysis]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
[[Category: Serine protease]] | [[Category: Serine protease]] | ||
Revision as of 10:18, 21 December 2014
Crystal structure of human granzyme HCrystal structure of human granzyme H
Structural highlights
Publication Abstract from PubMedHuman 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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