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Crystal structure of ClfA in complex with the Fab fragment of Tefibazumab
Structural highlights
FunctionCLFA_STAAE Cell surface-associated protein implicated in virulence. Promotes bacterial attachment exclusively to the gamma-chain of human fibrinogen. Induces formation of bacterial clumps, which diminish the ability of group IIA phospholipase A2 to cause bacterial phospholipid hydrolysis and killing. Significantly decreases macrophage phagocytosis possibly thanks to the clumps, clumped bacteria being too large to be phagocytosed. Dominant factor responsible for human platelet aggregation, which may be an important mechanism for initiating infective endocarditis. Enhances spleen cell proliferative response in vitro, contributing significantly to the immunostimulatory activity of S.aureus.[1] [2] [3] [4] Publication Abstract from PubMedThe Staphylococcus aureus fibrinogen binding MSCRAMM (Microbial Surface Components Recognizing Adhesive Matrix Molecules), ClfA (clumping factor A) is an important virulence factor in staphylococcal infections and a component of several vaccines currently under clinical evaluation. The mouse monoclonal antibody aurexis (also called 12-9), and the humanized version tefibazumab are therapeutic monoclonal antibodies targeting ClfA that in combination with conventional antibiotics were effective in animal models but showed less impressive efficacy in a limited Phase II clinical trial. We here report the crystal structure and a biochemical characterization of the ClfA/tefibazumab (Fab) complex. The epitope for tefibazumab is located to the "top" of the N3 subdomain of ClfA and partially overlaps with a previously unidentified second binding site for fibrinogen. A high-affinity binding of ClfA to fibrinogen involves both an interaction at the N3 site and the previously identified docking of the C-terminal segment of the fibrinogen gamma-chain in the N2N3 trench. Although tefibazumab binds ClfA with high affinity we observe a modest IC50 value for the inhibition of fibrinogen binding to the MSCRAMM. This observation, paired with a common natural occurring variant of ClfA that is not effectively recognized by the mAb, may partly explain the modest effect tefibazumab showed in the initial clinic trail. This information will provide guidance for the design of the next generation of therapeutic anti-staphylococcal mAbs targeting ClfA. Lessons from the Crystal Structure of the S. aureus Surface Protein Clumping Factor A in Complex With Tefibazumab, an Inhibiting Monoclonal Antibody.,Ganesh VK, Liang X, Geoghegan JA, Cohen AL, Venugopalan N, Foster TJ, Hook M EBioMedicine. 2016 Nov;13:328-338. doi: 10.1016/j.ebiom.2016.09.027. Epub 2016, Oct 1. PMID:27789272[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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