The 2.0 Angstrom resolution crystal structure of the retro-binding natural product nazumamide A (NAZA) complexed with human thrombin is presented. The crystal structure shows that the retro-binding nazumamide A is noncleavable and extends into the prime end of the substrate binding cleft. The data suggest ideas for SAR and combinatorial modification of nazumamide A to create a second generation of nazumamide-like compounds which are potent and specific for human thrombin. This crystal structure indicates that fresh ideas for the generation of novel and specific inhibitors may arise from examining weak binding compounds. Additionally, the crystal structure demonstrates the utility of crystallographic analysis of natural product:protein complexes.