A structural basis for complement inhibition by Staphylococcus aureus

Hammel, Michal; Sfyroera, Georgia; Ricklin, Daniel; Magotti, Paola; Lambris, John D.; Geisbrecht, Brian V.

doi:10.1038/ni1450

Cited by 152 publications

(287 citation statements)

References 41 publications

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“…According to our previous studies, the C3-inhibitory domain of Efb or Efb-C is comprised of three canonical ␣ helices (N-terminal ␣1 helix from K106 to H125, short loop ␣2 helix from V127 to L139 and C-terminal ␣3 helix from K145 to Q161) and a randomly coiled terminus from G162 to R165 [26]. As depicted in Figure 5, each of the Efb-C helices donates one or more residues that contact C3d.…”

Section: Resultsmentioning

confidence: 99%

“…Recombinant Efb, Efb-C, and C3d were prepared in a manner identical to that used for crystallization and structure/function studies [26]. Chymotrypsin and glutamic-C V8 were purchased from Princeton Separations, Inc. (Adelphia, NJ).…”

Section: Methodsmentioning

confidence: 99%

“…As a consequence, the potential contributions of these N-terminal regions to complement inhibition remain largely unexplored. In this particular case, even transiently stable interactions between Efb and C3 may be biologically relevant since binding of Efb-C is known to effect to the solution conformation of C3 [26]. Furthermore, proteins may adopt conformations in solution that differ in small but important aspects from those observed in accurately refined crystal structures.…”

mentioning

confidence: 99%

“…To gain insight into the mechanism of Efb function, we recently determined the crystal structure of its C3-inhibitory domain (denoted Efb-C) both free and bound to its cognate C3d subdomain from human C3 [26]. These structures revealed that Efb-C adopts a novel three helix bundle motif involved in complement regulation and provided insight into the proteinprotein interaction network that targets Efb to the surface of C3.…”

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confidence: 99%

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Solution insights into the structure of the Efb/C3 complement inhibitory complex as revealed by lysine acetylation and mass spectrometry

Chen

Schuster

Sfyroera

et al. 2008

J. Am. Soc. Mass Spectrom.

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The extracellular fibrinogen-binding protein (Efb), an immunosuppressive and anti-inflammatory protein secreted by Staphylococcus aureus, has been identified as a potent inhibitor of complement-mediated innate immunity. Efb functions by binding to and disrupting the function of complement component 3 (C3). In a recent study, we presented a high-resolution co-crystal structure of the complement inhibitory domain of Efb (Efb-C) bound to its cognate domain (C3d) from human C3 and employed a series of structure/function analyses that provided evidence for an entirely new, conformational change-based mechanism of complement inhibition. To better understand the Efb/C3 complex and its downstream effects on C3 inhibition, we investigated the solvent-accessibility and protein interface of Efb(-C)/C3d using a method of lysine acetylation, proteolytic digestion, and mass spectrometric analysis. Lysine modification in Efb was monitored by the mass increment of lysine-containing fragments. Besides confirming the binding sites observed in co-crystal structure study, the in-solution data presented here suggest additional contacting point(s) between the proteins that were not revealed by crystallography. The results of this study demonstrate that solution-based analysis of protein-protein interactions can provide important complementary information on the nature of protein-protein interactions. (J Am Soc Mass Spectrom 2008, 19, 55-65)

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Solution insights into the structure of the Efb/C3 complement inhibitory complex as revealed by lysine acetylation and mass spectrometry

Chen

Schuster

Sfyroera

et al. 2008

J. Am. Soc. Mass Spectrom.

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“…In particular, the extracellular fibrinogen-binding protein (Efb) and the related Efbhomologous protein (Ehp) from Staphylococcus aureus have been found to efficiently inhibit complement activation by binding to native C3 and all its fragments that contain the thioester domain (Hammel et al 2007a,b). This binding induces a conformational change in both C3 and C3b and therefore influences the conversion of C3 and C5 by the corresponding convertases (Hammel et al 2007b;Jongerius et al 2007). While the bacterial proteins themselves may be too immunogenic for a direct use as therapeutics, they may be used as templates for developing complement-inhibiting drugs.…”

Section: Discussionmentioning

confidence: 99%

Compstatin: A Complement Inhibitor on its Way to Clinical Application

Ricklin

Lambris²

2008

Advances in Experimental Medicine and Biology

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Therapeutic modulation of the human complement system is considered a promising approach for treating a number of pathological conditions. Owing to its central position in the cascade, component C3 is a particularly attractive target for complement-specific drugs. Compstatin, a cyclic tridecapeptide, which was originally discovered from phage-display libraries, is a highly potent and selective C3 inhibitor that demonstrated clinical potential in a series of experimental models. A combination of chemical, biophysical, and computational approaches allowed a remarkable optimization of its binding affinity towards C3 and its inhibitory potency. With the recent announcement of clinical trials with a compstatin analog for the treatment of age-related macular degeneration, another important milestone has been reached on its way to a drug. Furthermore, the release of a co-crystal structure of compstatin with C3c allows a detailed insight into the binding mode and paves the way to the rational design of peptides and mimetics with improved activity. Considering the new incentives and the promising pre-clinical results, compstatin seems to be well equipped for the challenges on its way to a clinical therapeutic. Tackling Complement at its CoreTherapeutic intervention in the human complement system has long been recognized as a promising strategy for the treatment of a series of ischemic, inflammatory and autoimmune diseases (Lambris and Holers 2000;Ricklin and Lambris 2007a). In principle, the large network of soluble and cell-surface-bound proteins, which builds the base of the complement cascade, offers a variety of potential drug targets. However, the quest for complement-specific therapeutics proved to be much more challenging than initially anticipated. With the therapeutic antibody eculizumab (Soliris ® , Alexion Pharmaceuticals, Inc.) against paroxysmal nocturnal hemoglobinuria, the first drug with proven complement connectivity has been marketed only recently (Ricklin and Lambris 2007a;Rother et al. 2007). A second complement-associated compound, purified C1 esterase inhibitor (C1-INH), is available as a therapeutic option for the treatment of hereditary angioedema in several countries. However, its mechanism of action may be closer related to the bradykinin-kallikrein than the complement cascade (Davis 2006). Strikingly, both drugs cover relatively rare diseases and have been developed with the aid of orphan drug regulations. Yet, for many of the more common inflammatory or autoimmune conditions there are no complement drugs on the market. Any extension of the current complement-specific therapeutic arsenal is therefore highly desired.Part of the problem in complement-directed drug discovery is the selection of the right target (Ricklin and Lambris 2007a activation is considered to be the most promising approach in many cases. On a molecular level, inhibition at the level of C3, including the C3 convertases, is of particular interest since both the amplification of all initiation pathways and the generatio...

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Pathogenesis of Staphylococcus aureus in Humans

DeLeo

2015

Human Emerging and Re‐emerging Infections

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A structural basis for complement inhibition by Staphylococcus aureus

Cited by 152 publications

References 41 publications

Solution insights into the structure of the Efb/C3 complement inhibitory complex as revealed by lysine acetylation and mass spectrometry

Solution insights into the structure of the Efb/C3 complement inhibitory complex as revealed by lysine acetylation and mass spectrometry

Compstatin: A Complement Inhibitor on its Way to Clinical Application

Pathogenesis of Staphylococcus aureus in Humans

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