1y7k
From Proteopedia
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|ACTIVITY= | |ACTIVITY= | ||
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1hyk|1HYK]], [[1mr0|1MR0]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1y7k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1y7k OCA], [http://www.ebi.ac.uk/pdbsum/1y7k PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1y7k RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
Expression of the agouti signaling protein (ASIP) during hair growth produces the red/yellow pigment pheomelanin. ASIP, and its neuropeptide homolog the agouti-related protein (AgRP) involved in energy balance, are novel, paracrine signaling molecules that act as inverse agonists at distinct subsets of melanocortin receptors. Ubiquitous ASIP expression in mice gives rise to a pleiotropic phenotype characterized by a uniform yellow coat color, obesity, overgrowth, and metabolic derangements similar to type II diabetes in humans. Here we report the synthesis and NMR structure of ASIP's active, cysteine-rich, C-terminal domain. ASIP adopts the inhibitor cystine knot fold and, along with AgRP, are the only known mammalian proteins in this structure class. Moreover, ASIP populates two distinct conformers resulting from a cis peptide bond at Pro102-Pro103 and a coexistence of cis/trans isomers of Ala104-Pro105. Pharmacologic studies of Pro-->Ala mutants demonstrate that the minor conformation with two cis peptide bonds is responsible for activity at all MCRs. The loop containing the heterogeneous Ala-Pro peptide bond is conserved in mammals, and suggests that ASIP is either trapped by evolution in this unusual configuration or possesses function outside of strict MCR antagonism. | Expression of the agouti signaling protein (ASIP) during hair growth produces the red/yellow pigment pheomelanin. ASIP, and its neuropeptide homolog the agouti-related protein (AgRP) involved in energy balance, are novel, paracrine signaling molecules that act as inverse agonists at distinct subsets of melanocortin receptors. Ubiquitous ASIP expression in mice gives rise to a pleiotropic phenotype characterized by a uniform yellow coat color, obesity, overgrowth, and metabolic derangements similar to type II diabetes in humans. Here we report the synthesis and NMR structure of ASIP's active, cysteine-rich, C-terminal domain. ASIP adopts the inhibitor cystine knot fold and, along with AgRP, are the only known mammalian proteins in this structure class. Moreover, ASIP populates two distinct conformers resulting from a cis peptide bond at Pro102-Pro103 and a coexistence of cis/trans isomers of Ala104-Pro105. Pharmacologic studies of Pro-->Ala mutants demonstrate that the minor conformation with two cis peptide bonds is responsible for activity at all MCRs. The loop containing the heterogeneous Ala-Pro peptide bond is conserved in mammals, and suggests that ASIP is either trapped by evolution in this unusual configuration or possesses function outside of strict MCR antagonism. | ||
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| - | ==Disease== | ||
| - | Known diseases associated with this structure: Canavan disease OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608034 608034]], Skin/hair/eye pigmentation 9, dark/light hair OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600201 600201]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Millhauser, G L.]] | [[Category: Millhauser, G L.]] | ||
[[Category: Thompson, D A.]] | [[Category: Thompson, D A.]] | ||
| - | [[Category: | + | [[Category: cystine knot]] |
| + | [[Category: endogenous antagonist]] | ||
| + | [[Category: gpcr]] | ||
| + | [[Category: inhibitor]] | ||
| + | [[Category: inverse agonist]] | ||
| + | [[Category: melanocortin]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:59:47 2008'' |
Revision as of 21:59, 30 March 2008
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| Related: | 1HYK, 1MR0
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
NMR structure family of Human Agouti Signalling Protein (80-132: Q115Y, S124Y)
Overview
Expression of the agouti signaling protein (ASIP) during hair growth produces the red/yellow pigment pheomelanin. ASIP, and its neuropeptide homolog the agouti-related protein (AgRP) involved in energy balance, are novel, paracrine signaling molecules that act as inverse agonists at distinct subsets of melanocortin receptors. Ubiquitous ASIP expression in mice gives rise to a pleiotropic phenotype characterized by a uniform yellow coat color, obesity, overgrowth, and metabolic derangements similar to type II diabetes in humans. Here we report the synthesis and NMR structure of ASIP's active, cysteine-rich, C-terminal domain. ASIP adopts the inhibitor cystine knot fold and, along with AgRP, are the only known mammalian proteins in this structure class. Moreover, ASIP populates two distinct conformers resulting from a cis peptide bond at Pro102-Pro103 and a coexistence of cis/trans isomers of Ala104-Pro105. Pharmacologic studies of Pro-->Ala mutants demonstrate that the minor conformation with two cis peptide bonds is responsible for activity at all MCRs. The loop containing the heterogeneous Ala-Pro peptide bond is conserved in mammals, and suggests that ASIP is either trapped by evolution in this unusual configuration or possesses function outside of strict MCR antagonism.
About this Structure
1Y7K is a Single protein structure of sequence from [1]. Full crystallographic information is available from OCA.
Reference
Structures of the agouti signaling protein., McNulty JC, Jackson PJ, Thompson DA, Chai B, Gantz I, Barsh GS, Dawson PE, Millhauser GL, J Mol Biol. 2005 Mar 4;346(4):1059-70. Epub 2005 Jan 25. PMID:15701517
Page seeded by OCA on Mon Mar 31 00:59:47 2008
