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Loops and Links: Structural Insights into the Remarkable Function of the Agouti-Related Protein

dc.contributor.authorMillhauser, Glenn L.en_US
dc.contributor.authorMcNulty, Joe C.en_US
dc.contributor.authorJackson, Pilgrim J.en_US
dc.contributor.authorThompson, Darren A.en_US
dc.contributor.authorBarsh, Gregory S.en_US
dc.contributor.authorGantz, Iraen_US
dc.date.accessioned2010-06-01T22:46:51Z
dc.date.available2010-06-01T22:46:51Z
dc.date.issued2003-06en_US
dc.identifier.citationMILLHAUSER, GLENN L.; McNULTY, JOE C.; JACKSON, PILGRIM J.; THOMPSON, DARREN A.; BARSH, GREGORY S.; GANTZ, IRA (2003). "Loops and Links: Structural Insights into the Remarkable Function of the Agouti-Related Protein." Annals of the New York Academy of Sciences 994(1 THE MELANOCORTIN SYSTEM ): 27-35. <http://hdl.handle.net/2027.42/75746>en_US
dc.identifier.issn0077-8923en_US
dc.identifier.issn1749-6632en_US
dc.identifier.urihttps://hdl.handle.net/2027.42/75746
dc.identifier.urihttp://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=12851295&dopt=citationen_US
dc.description.abstractThe agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin receptors MC3R and MC4R found in the hypothalamus and exhibits potent orexigenic activity. The cysteine-rich C-terminal domain of this protein, corresponding to AGRP(87–132), exhibits receptor binding affinity and antagonism equivalent to that of the full-length protein. We recently determined the NMR structure of AGRP(87–132) and demonstrated that a portion of the domain adopts the inhibitor cystine-knot fold. Remarkably, this is the first identification of a mammalian protein with this specific architecture. Further analysis of the structure suggests that melanocortin receptor contacts are made primarily by two loops presented within the cystine knot. 10 To test this hypothesis we designed a 34-residue AGRP analogue corresponding to only the cystine knot. We found that this designed miniprotein folds to a homogeneous product, retains the desired cystine-knot architecture, functions as a potent antagonist, and maintains the melanocortin receptor pharmacological profile of AGRP(87–132). 26 The AGRP-like activity of this molecule supports the hypothesis that indeed the cystine-knot region possesses the melanocortin receptor contacts. Based on these design and structure studies, we propose that the N-terminal loop of AGRP(87–132) makes contact with a receptor exoloop and helps confer AGRP's selectivity for the central MCRs.en_US
dc.format.extent4212163 bytes
dc.format.extent3109 bytes
dc.format.mimetypeapplication/pdf
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dc.publisherBlackwell Publishing Ltden_US
dc.rights2003 New York Academy of Sciencesen_US
dc.subject.otherMelanocortin Receptoren_US
dc.subject.otherAgouti-related Proteinen_US
dc.subject.otherNuclear Magnetic Resonanceen_US
dc.titleLoops and Links: Structural Insights into the Remarkable Function of the Agouti-Related Proteinen_US
dc.typeArticleen_US
dc.subject.hlbsecondlevelScience (General)en_US
dc.subject.hlbtoplevelScienceen_US
dc.description.peerreviewedPeer Revieweden_US
dc.contributor.affiliationumDepartment of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USAen_US
dc.contributor.affiliationotherDepartment of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, USAen_US
dc.contributor.affiliationotherHoward Hughes Medical Institute and the Department of Pediatrics and Genetics, Stanford University Medical Center, Stanford, Califorrnia 94305, USAen_US
dc.identifier.pmid12851295en_US
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/75746/1/j.1749-6632.2003.tb03159.x.pdf
dc.identifier.doi10.1111/j.1749-6632.2003.tb03159.xen_US
dc.identifier.sourceAnnals of the New York Academy of Sciencesen_US
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dc.owningcollnameInterdisciplinary and Peer-Reviewed


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