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Protein Sci. 2008 Nov;17(11):1894-906. doi: 10.1110/ps.036624.108. Epub 2008 Aug 7.

Electrostatic contributions drive the interaction between Staphylococcus aureus protein Efb-C and its complement target C3d.

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1
Department of Computer Science, Rice University, Houston, Texas 77005, USA.

Abstract

The C3-inhibitory domain of Staphylococcus aureus extracellular fibrinogen-binding protein (Efb-C) defines a novel three-helix bundle motif that regulates complement activation. Previous crystallographic studies of Efb-C bound to its cognate subdomain of human C3 (C3d) identified Arg-131 and Asn-138 of Efb-C as key residues for its activity. In order to characterize more completely the physical and chemical driving forces behind this important interaction, we employed in this study a combination of structural, biophysical, and computational methods to analyze the interaction of C3d with Efb-C and the single-point mutants R131A and N138A. Our results show that while these mutations do not drastically affect the structure of the Efb-C/C3d recognition complex, they have significant adverse effects on both the thermodynamic and kinetic profiles of the resulting complexes. We also characterized other key interactions along the Efb-C/C3d binding interface and found an intricate network of salt bridges and hydrogen bonds that anchor Efb-C to C3d, resulting in its potent complement inhibitory properties.

PMID:
18687868
PMCID:
PMC2578803
DOI:
10.1110/ps.036624.108
[Indexed for MEDLINE]
Free PMC Article
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