4h6i

Crystal Structure of Staphylococcal Complement Inhibitor SCIN-B

spinqualitylabelsall models 4h6i, resolution 3.09Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4h6i is a 3 chain structure with sequence from Staphylococcus aureus subsp. aureus Mu50. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A0H3JZ23_STAAM Involved in countering the first line of host defense mechanisms. Efficiently inhibits opsonization, phagocytosis and killing of S.aureus by human neutrophils. Acts by binding and stabilizing human C3 convertases (C4b2a and C3bBb), leading to their inactivation. The convertases are no longer able to cleave complement C3, therefore preventing further C3b deposition on the bacterial surface and phagocytosis of the bacterium. Also prevents C5a-induced neutrophil responses.[ARBA:ARBA00025334] Publication Abstract from PubMed Complement is a network of interacting circulatory and cell-surface proteins that recognizes, marks, and facilitates clearance of microbial invaders. To evade complement attack, the pathogenic organism Staphylococcus aureus expresses a number of secreted proteins that interfere with activation and regulation of the complement cascade. Staphylococcal Complement Inhibitors (SCINs) are one important class of these immunomodulators and consist of three active members (SCIN-A/-B/-C). SCINs inhibit a critical enzymatic complex, the alternative pathway C3 convertase, by targeting a functional hotspot on the central opsonin of complement, C3b. Although N-terminal truncation mutants of SCINs retain complement inhibitory properties they are significantly weaker binders of C3b. To provide a structural basis for this observation, we undertook a series of crystallographic and NMR dynamics studies on full-length SCINs. This work reveals that N-terminal SCIN domains are characterized by a conformationally dynamic helical motif. C3b-binding and functional experiments further demonstrate that this sequence divergent N-terminal region of SCINs is both functionally important and context-dependent. Finally, surface plasmon resonance data provide evidence for the formation of inhibitor/enzyme/substrate complexes ((SCIN/C3bBb)/C3). Similar to the (SCIN/C3bBb)2 psuedo-dimeric complexes, ((SCIN/C3bBb)/C3) interferes with the interaction of complement receptors and C3b. This activity provides an additional mechanism by which SCIN couples convertase inhibition to direct blocking of phagocytosis. Together these data suggest that tethering multi-host-protein complexes by small modular bacterial inhibitors may be a global strategy of immune evasion employed by S. aureus. The work presented here provides detailed structure-activity relationships and improves our understanding of how S. aureus circumvents human innate immunity. A structurally dynamic N-terminal helix is a key functional determinant in Staphylococcal Complement Inhibitor (SCIN) proteins.,Garcia BL, Summers BJ, Ramyar KX, Tzekou A, Lin Z, Ricklin D, Lambris JD, Laity JH, Geisbrecht BV J Biol Chem. 2012 Dec 11. PMID:23233676 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Fibrinogen binding protein

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