1ORF

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

Summary for 1ORF

• Entry DOI: 10.2210/pdb1orf/pdb
• Related PRD ID: PRD_000020
• Descriptor: 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)
• Functional Keywords: hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Isoform alpha: Secreted: P12544
• Total number of polymer chains: 1
• Total formula weight: 26420.11

Authors

Bell, J.K.,Goetz, D.H.,Mahrus, S.,Harris, J.L.,Fletterick, R.J.,Craik, C.S. (deposition date: 2003-03-12, release date: 2003-07-01, Last modification date: 2024-11-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.4 Å)