LEP and obesity due to melanocortin 4 receptor deficiency: Although most obesity-associated mutations in LepR are distal to the leptin-binding sites and likely act to simply destabilize LepR, two previously identified human obesity-associated LepR mutations (A409E and Y422H)22,23 both occur at the site 3 binding interface and are predicted by our structure to disrupt the key aromatic contacts formed by leptin Tyr119 (Fig. 3f).