Significance Proteins embedded in membranes experience anisotropic forces from their surroundings. Mechanosensors are activated upon changes in the membrane tension and are the basis of important biological functionalities. However, the molecular mechanisms of mechanosensation are only vaguely understood. Hydrophobic mismatch between protein and membrane, amphiphilic sliding helices, or local membrane bending are examples for different concepts explaining mechanosensation in which one or more of these concepts could be implemented in a particular protein. Here, we show that the mechanosensitive channel of small conductance is gated by the extrusion of lipids from hydrophobic pockets independent of the membrane. A cryoelectron microscopy map at 2.3-Å resolution reveals the so-far-neglected role of aliphatic chains at the periplasmatic side in stabilizing the open state.