The proof is in the crystal.

In this issue of Blood, McEwan and colleagues describe the structure of a complex between GPIb and a small-molecule antagonist and elucidate a novel allosteric mechanism for targeting this receptor’s interaction with von Willebrand factor.1 In recent years, platelet receptors have been successfully targeted by small-molecule antithrombotic drugs, with the integrin IIb 3 and the G-protein– coupled receptor P2Y12 being prime examples. Of the two, P2Y12 is a much more traditional small-molecule target, with drugs such as clopidogrel and prasugrel interfering with the ability of another small molecule, adenosine diphosphate, to signal to induce platelet aggregation. A priori, targeting the interaction of IIb 3 with either fibrinogen or von Willebrand factor (VWF) would seem much more problematic, the small molecule having to disrupt the interaction of 2 very large proteins. In this case, however, the problem is simplified by the fact that short, continuous stretches of amino acids (Arg-Gly-Asp-Ser, RGDS, in both fibrinogen and VWF, and the related HHLGGAKQAGDV -chain sequence in fibrinogen) make up the primary binding sites for IIb 3 on these ligands; this formed the basis of strategies to target the receptor. Eptifibatide, an IIb 3 antagonist that is based on a sequence from the pit viper protein barbourin, contains a (KGD) sequence with greater specificity for IIb 3 than the canonical RGD sequence.2 However, only a relatively small percentage of protein-protein interactions have such small interaction “hot spots” that contribute so much to the total binding energy of the interaction.2 The interaction between glycoprotein (GP) Ib and VWF, which mediates the first step of platelet adhesion to sites of vessel injury, seems a particularly difficult small-molecule target, given that the interactive surface between this receptorligand pair covers 2600 Å,3 an enormous area for a small molecule to cover.4 Within these 2 large proteins the interaction sites reside in smaller domains, in GPIb in a 290 – amino acid sequence at the polypeptide’s N-terminus, and in VWF entirely within the 186 –amino acid A1 domain. In this region of GPIb , important sequences include an Nterminal disulfide loop known as the -finger, and a C-terminal disulfide loop called the -switch or regulatory (R)-loop (see figure). N-terminus