FIGURE 3. Four comparisons of how a protein interacts with its natural protein (or peptide) partner and with a synthetic small molecule.

The structures of protein–protein or protein–peptide complexes are shown on the left. The target protein is rendered as a filled surface (grey), and the binding protein or peptide is represented as a ribbon diagram (yellow), with selected side chains shown as sticks (with carbon in yellow, oxygen in red and nitrogen in blue). The contact surface on the target protein (within 4.5 Å of the binding partner) is shown in green. The structures of the protein–small-molecule complexes are shown on the right. The small molecule is shown in stick format, and the contact surface is shown in orange. In the centre, small molecules are shown superimposed on the protein in the conformation in which it binds to its natural protein or peptide partner, and the contact surface (on the target protein) of the natural interaction is shown in green. From these examples, it is clear that the protein–protein contact surface is much larger and flatter than the protein–small-molecule contact surface. a, IL-2 bound to its natural protein partner IL-2R (left), and IL-2 bound to the small molecule SP4206 (right). b, Bcl-XL bound to a peptide derived from one of its natural protein partners, BAD, and Bcl-XL bound to the small molecule ABT-737. c, HDM2 bound to a peptide derived from its natural protein partner p53, and HDM2 bound to the small molecule Nutlin-2 (upper) or a benzodiazepinedione (lower). d, HPV-18 E2 bound to HPV-18 E1, and HPV-11 E2 bound to the small molecule compound 18. The centre panel is not shown, because HPV-18 and HPV-11 are related but not identical. Images generated from files from the PDB, as indicated in Table 1.