Inward rectifier potassium (Kir) channel activity is controlled by plasma membrane lipids. Phosphatidylinositol- 4,5-bisphosphate (PIP2) binding to a primary site is required for opening of classic inward rectifier Kir2.1 and Kir2.2 channels, but interaction of bulk anionic phospholipid (PL-) with a distinct second site is required for high PIP2sensitivity. Here we show that introduction of a lipid-partitioning tryptophan at the second site (K62W) generates high PIP2sensitivity, even in the absence of PL-. Furthermore, high-resolution x-ray crystal structures of Kir2.2[K62W], with or without added PIP2 (2.8- and 2.0-Å resolution, respectively), reveal tight tethering of the C-terminal domain (CTD) to the transmembrane domain (TMD) in each condition. Our results suggest a refined model for phospholipid gating in which PL- binding at the second site pulls the CTD toward the membrane, inducing the formation of the high-affinity primary PIP2site and explaining the positive allostery between PL- binding and PIP2sensitivity.