3TJV

Crystal structure of human granzyme H with a peptidyl substrate

3TJV の概要

• エントリーDOI: 10.2210/pdb3tjv/pdb
• 関連するPDBエントリー: 3TJU 3TK9
• 分子名称: Granzyme H, PTSYAGDDSG, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: serine protease, cytolysis, hydrolase substrate, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cytoplasmic granule: P20718
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 26372.48

構造登録者

Wang, L.,Zhang, K.,Wu, L.,Tong, L.,Sun, F.,Fan, Z. (登録日: 2011-08-25, 公開日: 2011-12-28, 最終更新日: 2024-10-16)

主引用文献

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

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: 22156497
DOI: 10.4049/jimmunol.1101381

実験手法

X-RAY DIFFRACTION (2.4 Å)