4NZL

Extracellular proteins of Staphylococcus aureus inhibit the neutrophil serine proteases

Summary for 4NZL

• Entry DOI: 10.2210/pdb4nzl/pdb
• Descriptor: Neutrophil elastase, Uncharacterized protein, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[beta-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: primarily beta, serine protease, protease inhibitor, innate immunity, azurophilic granules, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Staphylococcus aureus subsp. aureus; More
• Total number of polymer chains: 2
• Total formula weight: 37506.63

Authors

Stapels, D.A.C.,von Koeckritz-Blickwede, M.,Ramyar, K.X.,Bischoff, M.,Milder, F.,Ruyken, M.,Scheepmaker, L.,McWhorter, W.J.,Herrmann, M.,van Kessel, K.P.M.,Geisbrecht, B.V.,Rooijakkers, S.H.M. (deposition date: 2013-12-12, release date: 2014-08-20, Last modification date: 2024-10-09)

Primary citation

Stapels, D.A.,Ramyar, K.X.,Bischoff, M.,von Kockritz-Blickwede, M.,Milder, F.J.,Ruyken, M.,Eisenbeis, J.,McWhorter, W.J.,Herrmann, M.,van Kessel, K.P.,Geisbrecht, B.V.,Rooijakkers, S.H.
Staphylococcus aureus secretes a unique class of neutrophil serine protease inhibitors.
Proc.Natl.Acad.Sci.USA, 111:13187-13192, 2014

PubMed Abstract: Neutrophils are indispensable for clearing infections with the prominent human pathogen Staphylococcus aureus. Here, we report that S. aureus secretes a family of proteins that potently inhibits the activity of neutrophil serine proteases (NSPs): neutrophil elastase (NE), proteinase 3, and cathepsin G. The NSPs, but not related serine proteases, are specifically blocked by the extracellular adherence protein (Eap) and the functionally orphan Eap homologs EapH1 and EapH2, with inhibitory-constant values in the low-nanomolar range. Eap proteins are together essential for NSP inhibition by S. aureus in vitro and promote staphylococcal infection in vivo. The crystal structure of the EapH1/NE complex showed that Eap molecules constitute a unique class of noncovalent protease inhibitors that occlude the catalytic cleft of NSPs. These findings increase our insights into the complex pathogenesis of S. aureus infections and create opportunities to design novel treatment strategies for inflammatory conditions related to excessive NSP activity.

PubMed: 25161283
DOI: 10.1073/pnas.1407616111

Experimental method

X-RAY DIFFRACTION (1.85 Å)