3TK9
Crystal structure of human granzyme H
Summary for 3TK9
| Entry DOI | 10.2210/pdb3tk9/pdb |
| Related | 3TJU 3TJV |
| Descriptor | Granzyme H, SULFATE ION (3 entities in total) |
| Functional Keywords | serine protease, hydrolase, cytolysis |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasmic granule: P20718 |
| Total number of polymer chains | 1 |
| Total formula weight | 25307.49 |
| Authors | |
| Primary citation | 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., 188:765-773, 2012 Cited by PubMed Abstract: 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 Å, 2.4 Å, and 2.7 Å, 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. PubMed: 22156497DOI: 10.4049/jimmunol.1101381 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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