We present the first structure of human aldosterone synthase (CYP11B2) in complex with the Cushing’s disease drug LCI699, a derivative of the breast cancer drug fadrozole. Our studies also include an examination of affinity and inhibition of fadrozole derivatives with recombinant proteins. Primary aldosteronism is the most common form of hypertension and derives from aldosterone overproduction by CYP11B2. Treatment is impeded due to the high sequence similarity to cortisol-producing CYP11B1. We identified crucial differences in the active site architecture to cortisol-producing CYP11B1 and demonstrate the flexibility of the CYP11B2 active site dependent on inhibitor size. Differences in CYP11B active site architecture can be exploited for directed drug design for the treatment of primary aldosteronism.
