1hyk

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AGOUTI-RELATED PROTEIN (87-132) (AC-AGRP(87-132))

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The structure of the chemically synthesized C-terminal region of the human agouti related protein (AGRP) was determined by 2D 1H NMR. Referred to as minimized agouti related protein, MARP is a 46 residue polypeptide containing 10 Cys residues involved in five disulfide bonds that retains the biological activity of full length AGRP. AGRP is a mammalian signaling molecule, involved in weight homeostasis, that causes adult onset obesity when overexpressed in mice. AGRP was originally identified by homology to the agouti protein, another potent signaling molecule involved in obesity disorders in mice. While AGRP's exact mechanism of action is unknown, it has been identified as a competitive antagonist of melanocortin receptors 3 and 4 (MC3r, MC4r), and MC4r in particular is implicated in the hypothalamic control of feeding behavior. Full length agouti and AGRP are only 25% homologous, however, their active C-terminal regions are approximately 40% homologous, with nine out of the 10 Cys residues spatially conserved. Until now, 3D structures have not been available for either agouti, AGRP or their C-terminal regions. The NMR structure of MARP reported here can be characterized as three major loops, with four of the five disulfide bridges at the base of the structure. Though its fold is well defined, no canonical secondary structure is identified. While previously reported structural models of the C-terminal region of AGRP were attempted based on Cys homology between AGRP and certain toxin proteins, we find that Cys spacing is not sufficient to correctly determine the 3D fold of the molecule.

Disease

Known diseases associated with this structure: Leanness, inherited OMIM:[602311], Obesity, late-onset OMIM:[602311]

About this Structure

1HYK is a Single protein structure of sequence from [1]. This structure supersedes the now removed PDB entry 1QU8. Full crystallographic information is available from OCA.

Reference

NMR structure of a minimized human agouti related protein prepared by total chemical synthesis., Bolin KA, Anderson DJ, Trulson JA, Thompson DA, Wilken J, Kent SB, Gantz I, Millhauser GL, FEBS Lett. 1999 May 21;451(2):125-31. PMID:10371151

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