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. 2015 Sep 22;6:8277. doi: 10.1038/ncomms9277

Figure 2. Crystal structure of the KKO-Fab/PF4 tetramer complex.

Figure 2

(a,b) Overall structure of the PF4/KKO-Fab complex. a: cartoon representations of the complex; b: molecular surface representations. The heavy chain and light chain of KKO-Fab are coloured in blue and light blue, respectively. (c) Detailed binding interface of HIT antibody KKO to a PF4 tetramer. Residues within a PF4 tetramer that are <5 Å away from KKO-Fab molecule are highlighted. PF4 monomers are coloured as in Fig. 1. (d,e) Binding of KKO (d) and RTO (e) to structure-based PF4 mutants. (f) Platelet aggregation by wild-type PF4 and PF4 mutants. KKO (red) induced platelet aggregation in the presence of wild-type PF4 and heparin whereas an isotype matched non-pathogenic antibody RTO described below (green) did not. The panel also demonstrates that PF4 mutants bearing mutations along the KKO binding interface (blue, PF4-9SCV; brown, PF4-55R, Cyan, PF4-9SCV55R) were unable to mediate KKO-induced platelet aggregation. (g) Model of the KKO-Fab/PF4/heparin ternary complex. Surface representations of KKO-Fab are coloured in blue (heavy chain) and light blue (light chain) and others are coloured as in Fig. 1f. The model assumes the heparin molecule is composed of about 7 structures similar to fondaparinux depicted in the figure as a non-continuous chain. Intact UFH may further enhance the stability of the holo-complex compared with the fondaparinux fragment, thereby rendering it more antigenic and more capable of binding multiple IgG antibodies.