<p>Bitter taste functions as a means of both protection against potentially toxic compounds and savoring bitter tasting foods and beverages. Among the 26 bitter taste receptors, taste receptor type 2 member 43 (TAS2R43) has been identified as key for recognizing the bitter taste of coffee. TAS2R43 has also been implicated in many other physiological processes, including the regulation of glucagon-like peptide 1 release from the intestine, bronchodilation, innate immunity and metabolism. Here we report cryo-electron microscopy structures of human TAS2R43 coupled with inhibitory G protein or gustducin (G_gust) stabilized by the potent nephrotoxin and carcinogen aristolochic acid I. Both structures revealed that aristolochic acid I binds in a presumed orthosteric pocket shared with other bitter taste receptor. Further structural, functional and computational studies revealed potential modes for coffee’s constituents including caffeine and cafestol, which are bitter tastants from coffee. Lastly, long-timescale molecular dynamics simulations identified potential cryptic allosteric pockets in TAS2R43. These structures could accelerate the search for specific bitter taste ligands that ultimately may be therapeutically useful.</p>