The blockbuster blood-clot-preventing medication Plavix (clopidogrel) was discovered before researchers knew much about its biochemical target, which is a protein receptor called P2Y12. Today, however, they can at last see P2Y12’s structure, which could lead to next-generation drugs. Qiang Zhao of Shanghai Institute of Materia Medica teamed with Raymond C. Stevens of Scripps Research Institute California, Kenneth A. Jacobson of NIH, and their colleagues to solve P2Y12’s crystal structure (Nature 2014, DOI: 10.1038/nature13083 and 10.1038/nature13288). The researchers knew that P2Y12 is a G protein-coupled receptor, a protein that snakes across the cell membrane seven times. But they didn’t know that the conformation of its extracellular protein loops differs dramatically depending on whether P2Y12 is binding to an activator or an inactivator. What’s more, P2Y12 has two subpockets in its binding site, and none of the drugs that target the receptor takes advantage of both. Jacobson notes that chemists are seeking next-generation clot fighters that carry a lower risk of bleeding than established drugs. “Without these structures, we were working in the dark,” he says.