Structural and mechanistic paradigm of leptin receptor activation revealed by complexes with wild-type and antagonist leptins

Abstract

Leptin activates its cognate receptor (LR) to regulate body weight and metabolically costly processes, such as reproduction and immune responses. Despite such benevolent pleiotropy, leptin-mediated signaling has been implicated in autoimmune diseases and breast cancer, thereby rejuvenating interest in leptin antagonism. We present comparative biochemical and structural studies of the LR ectodomain (LRecto) in complex with wild-type and antagonist leptin variants. We show that high-affinity binding of leptin to the cytokine receptor ho Show more