Figure 1. Crystal structure of the fondaparinux/PF4 tetramer complex.

(a) Overall structure of the PF4/fondaparinux complex. Fondaparinux makes contacts with a single PF4 tetramer in the groove among the monomers on one side of the asymmetric tetramer. Monomers A, B, C and D in one PF4 tetramer are coloured in green, cyan, magenta and yellow, respectively. (b) Fondaparinux (stick representations) stabilizes the PF4 tetramer by binding in the groove among three monomers in a PF4 tetramer. Yellow dotted lines indicate the polar interactions between fondaparinux and three PF4 monomers. (c) One fondaparinux (spheres) denoted in the blue box binds in the groove of one tetramer (cartoon representation on the left) and also binds to the C-terminal helix of a second tetramer (cartoon representation on the right), thereby bridging PF4 tetramers. (d) Electrostatic potential surface representation (positive: blue; negative: red) of the PF4 tetramer shows that fondaparinux binds along a continuous positively charged surface on the ‘closed' side of PF4 tetramer. (e) Detailed representation of the positively charged residues (coloured in blue and labelled) on the fondaparinux binding interface between two PF4 tetramers. (f) Analysis of crystal lattice reveals a molecular pathway for the formation of antigenic complexes. A fragment of heparin first binds within the groove of one PF4 tetramer (limon, left); binding of the first PF4 tetramer imparts a local linearized structure on heparin, which enhances the binding of a second tetramer (pale green, middle); progression of this process eventuates in the formation of ultralarge antigenic complexes (right).