1ORF

The Oligomeric Structure of Human Granzyme A Reveals the Molecular Determinants of Substrate Specificity

1ORF の概要

• エントリーDOI: 10.2210/pdb1orf/pdb
• 関連するBIRD辞書のPRD_ID: PRD_000020
• 分子名称: Granzyme A, D-phenylalanyl-N-[(2S,3S)-6-{[amino(iminio)methyl]amino}-1-chloro-2-hydroxyhexan-3-yl]-L-prolinamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Isoform alpha: Secreted: P12544
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26420.11

構造登録者

Bell, J.K.,Goetz, D.H.,Mahrus, S.,Harris, J.L.,Fletterick, R.J.,Craik, C.S. (登録日: 2003-03-12, 公開日: 2003-07-01, 最終更新日: 2024-11-13)

主引用文献

Bell, J.K.,Goetz, D.H.,Mahrus, S.,Harris, J.L.,Fletterick, R.J.,Craik, C.S.
The oligomeric structure of human granzyme A is a determinant of its extended substrate specificity.
Nat.Struct.Biol., 10:527-534, 2003

PubMed Abstract: The cell death-inducing serine protease granzyme A (GzmA) has a unique disulfide-linked quaternary structure. The structure of human GzmA bound to a tripeptide CMK inhibitor, determined at a resolution of 2.4 A, reveals that the oligomeric state contributes to substrate selection by limiting access to the active site for potential macromolecular substrates and inhibitors. Unlike other serine proteases, tetrapeptide substrate preferences do not correlate well with natural substrate cleavage sequences. This suggests that the context of the cleavage sequence within a macromolecular substrate imposes another level of selection not observed with the peptide substrates. Modeling of inhibitors bound to the GzmA active site shows that the dimer also contributes to substrate specificity in a unique manner by extending the active-site cleft. The crystal structure, along with substrate library profiling and mutagenesis, has allowed us to identify and rationally manipulate key components involved in GzmA substrate specificity.

PubMed: 12819769
DOI: 10.1038/nsb944

実験手法

X-RAY DIFFRACTION (2.4 Å)