STRUCTURE OF THE COMPLEX OF AN FAB FRAGMENT OF A NEUTRALIZING ANTIBODY WITH FOOT-AND-MOUTH-DISEASE VIRUS - POSITIONING OF A HIGHLY MOBILE ANTIGENIC LOOP

Data from cryo-electron microscopy and X-ray crystallography have been combined to study the interactions of foot-and-mouth disease virus se rotype C (FMDV-C) with a strongly neutralizing monoclonal antibody (mA b) SD6. The mAb SDG binds to the long flexible GH-loop of viral protei n 1 (VP1) which also binds to an integrin receptor. The structure of t he virus-Fab complex was determined to 30 Angstrom resolution using cr yo-electron microscopy and image analysis. The known structure Of FMDV -C, and of the SD6 Fab co-crystallized with a synthetic peptide corres ponding to the GH-loop of VP1, were fitted to the cryo-electron micros cope density map. The SD6 Fab is seen to project almost radially from the viral surface in an orientation which is only compatible with mono valent binding of the mAb. Even taking into account the mAb hinge and elbow flexibility, it is not possible to model bivalent binding withou t severely distorting the Fabs. The bound GN-loop is essentially in wh at has previously been termed the 'up' position in the best fit Fab or ientation. The SD6 Fab interacts almost exclusively with the GN-loop o f VP1, making very few other contacts with the viral capsid. The posit ion and orientation of the SD6 Fab bound to FMDV-C is in accord with p revious immunogenic data.