Design, pharmacology, and NMR structure of a minimized cystine knot with agouti-related protein activity.

摘要: The agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin receptors MC3R and MC4R found in hypothalamus exhibits potent orexigenic activity. cysteine-rich C-terminal domain this protein, corresponding to AGRP(87-132), receptor binding affinity antagonism equivalent that full-length protein. NMR structure active was recently determined suggested contacts were made primarily by two loops presented a well-structured cystine knot within AGRP(87-132) [McNulty et al. (2001) Biochemistry 40, 15520-15527]. This hypothesis tested here with activity studies 34-residue AGRP analogue designed contain only domain. miniprotein folds homogeneous product, retains desired architecture, functions as antagonist, maintains pharmacological profile AGRP(87-132). AGRP-like molecule supports indeed region possesses contact points. Moreover, synthetically accessible, may serve development therapeutics for treatment diseases related energy balance. also find use new reagent probing function.