a structural model of the staphylococcus aureus clfa–fibrinogen interaction opens new avenues for the design of anti-staphylococcal therapeutics金黄色葡萄球菌clfa-fibrinogen交互的结构模型打开anti-staphylococcal疗法的设计的新途径.pdfVIP

A Structural Model of the Staphylococcus aureus ClfA– Fibrinogen Interaction Opens New Avenues for the Design of Anti-Staphylococcal Therapeutics 1. 1.¤a 1 1 1 Vannakambadi K. Ganesh , Jose J. Rivera , Emanuel Smeds , Ya-Ping Ko , M. Gabriela Bowden , 1 1¤b 2 ¨ ¨ 1 Elisabeth R. Wann , Shivasankarappa Gurusiddappa , J. Ross Fitzgerald , Magnus Hook * 1 Center for Extracellular Matrix Biology, Institute of Biosciences and Technology, Texas A M University Health Science Center, Houston, Texas, United States of America, 2 Centre for Infectious Diseases, School of Biomedical Sciences, The University of Edinburgh, Edinburgh, United Kingdom Abstract The fibrinogen (Fg) binding MSCRAMM Clumping factor A (ClfA) from Staphylococcus aureus interacts with the C-terminal region of the fibrinogen (Fg) c-chain. ClfA is the major virulence factor responsible for the observed clumping of S. aureus in blood plasma and has been implicated as a virulence factor in a mouse model of septic arthritis and in rabbit and rat models of infective endocarditis. We report here a high-resolution crystal structure of the ClfA ligand binding segment in complex with a synthetic peptide mimicking the binding site in Fg. The residues in Fg required for binding to ClfA are identified from this structure and from complementing biochemical studies. Furthermore, the platelet integrin aIIbb3 and ClfA bind to the same segment in the Fg c-chain but the two cellular binding proteins recognize different residues in the common targeted Fg segment. Based on these dif