4Q7Z

Neutrophil serine protease 4 (PRSS57) with phe-phe-arg-chloromethylketone (FFR-cmk)

Summary for 4Q7Z

• Entry DOI: 10.2210/pdb4q7z/pdb
• Related: 4Q7X 4Q7Y 4Q80
• Related PRD ID: PRD_001231
• Descriptor: Serine protease 57, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: trypsin homology, peptidase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasmic granule lumen : Q6UWY2
• Total number of polymer chains: 1
• Total formula weight: 28222.04

Authors

Eigenbrot, C.,Lin, S.J.,Dong, K.C. (deposition date: 2014-04-25, release date: 2014-09-03, Last modification date: 2023-09-20)

Primary citation

Lin, S.J.,Dong, K.C.,Eigenbrot, C.,van Lookeren Campagne, M.,Kirchhofer, D.
Structures of neutrophil serine protease 4 reveal an unusual mechanism of substrate recognition by a trypsin-fold protease.
Structure, 22:1333-1340, 2014

PubMed Abstract: Trypsin-fold proteases, the largest mammalian protease family, are classified by their primary substrate specificity into one of three categories, trypsin-like, chymotrypsin-like, and elastase-like, based on key structural features of their active site. However, the recently discovered neutrophil serine protease 4 (NSP4, also known as PRSS57) presents a paradox: NSP4 exhibits a trypsin-like specificity for cleaving substrates after arginine residues, but it bears elastase-like specificity determining residues in the active site. Here we show that NSP4 has a fully occluded S1 pocket and that the substrate P1-arginine adopts a noncanonical "up" conformation stabilized by a solvent-exposed H-bond network. This uncommon arrangement, conserved in all NSP4 orthologs, enables NSP4 to process substrates after both arginine as well as post-translationally modified arginine residues, such as methylarginine and citrulline. These findings establish a distinct paradigm for substrate recognition by a trypsin-fold protease and provide insights into the function of NSP4.

PubMed: 25156428
DOI: 10.1016/j.str.2014.07.008

Experimental method

X-RAY DIFFRACTION (1.4 Å)