Interfacial Binding Sites for Cholesterol on Kir, Kv, K_2P, and Related Potassium Channels

Inwardly rectifying, voltage-gated, two-pore domain, and related K⁺ channels are located in eukaryotic membranes rich in cholesterol. Here, molecular docking is used to detect specific binding sites ("hot spots") for cholesterol on K⁺ channels with characteristics that match those of known cholesterol binding sites. The transmembrane surfaces of all available high-resolution structures for K⁺ channels were swept for potential binding sites. Cholesterol poses were found to be located largely in hollows between protein ridges. A comparison between cholesterol poses and resolved phospholipids suggests that not all cholesterol molecules binding to the transmembrane surface of a K⁺ channel will result in displacement of a phospholipid molecule from the surface. Competition between cholesterol binding and binding of anionic phospholipids essential for activity could explain some of the effects of cholesterol on channel function.