Design, Pharmacology, and NMR Structure of a Minimized Cystine Knot with Agouti-Related Protein Activity

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• 作者：Pilgrim J. Jackson ; Joseph C. McNulty ; Ying-Kui Yang ; Darren A. Thompson ; Biaoxin Chai ; Ira Gantz ; Gregory S. Barsh ; and Glenn L. Millhauser
• 刊名：Biochemistry
• 出版年：2002
• 出版时间：June 18, 2002
• 年：2002
• 卷：41
• 期：24
• 页码：7565 - 7572
• 全文大小：181K
• 年卷期：v.41,no.24(June 18, 2002)
• ISSN：1520-4995

文摘

The agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin receptorsMC3R and MC4R found in the hypothalamus and exhibits potent orexigenic activity. The cysteine-richC-terminal domain of this protein, corresponding to AGRP(87-132), exhibits receptor binding affinityand antagonism equivalent to that of the full-length protein. The NMR structure of this active domainwas recently determined and suggested that melanocortin receptor contacts were made primarily by twoloops presented by a well-structured cystine knot domain within AGRP(87-132) [McNulty et al. (2001)Biochemistry 40, 15520-15527]. This hypothesis is tested here with NMR structure and activity studiesof a 34-residue AGRP analogue designed to contain only the cystine knot domain. The designed miniproteinfolds to a homogeneous product, retains the desired cystine knot architecture, functions as an antagonist,and maintains the melanocortin receptor pharmacological profile of AGRP(87-132). The AGRP-likeactivity of this molecule supports the hypothesis that indeed the cystine knot region possesses themelanocortin receptor contact points. Moreover, this potent AGRP analogue is synthetically accessible,may serve in the development of therapeutics for the treatment of diseases related to energy balance. andmay also find use as a new reagent for probing melanocortin receptor structure and function.