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==SOLUTION NMR STRUCTURE OF AGRP(87-120; C105A)==
==SOLUTION NMR STRUCTURE OF AGRP(87-120; C105A)==
<StructureSection load='1mr0' size='340' side='right' caption='[[1mr0]], [[NMR_Ensembles_of_Models | 40 NMR models]]' scene=''>
<StructureSection load='1mr0' size='340' side='right'caption='[[1mr0]]' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1mr0]] is a 1 chain structure. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=1mc6 1mc6]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MR0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1MR0 FirstGlance]. <br>
<table><tr><td colspan='2'>[[1mr0]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=1mc6 1mc6]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MR0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1MR0 FirstGlance]. <br>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1hyk|1hyk]], [[1mc6|1mc6]]</td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1mr0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1mr0 OCA], [http://pdbe.org/1mr0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1mr0 RCSB], [http://www.ebi.ac.uk/pdbsum/1mr0 PDBsum]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1mr0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1mr0 OCA], [https://pdbe.org/1mr0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1mr0 RCSB], [https://www.ebi.ac.uk/pdbsum/1mr0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1mr0 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/AGRP_HUMAN AGRP_HUMAN]] Genetic variations in AGRP may be a cause of obesity (OBESITY) [MIM:[http://omim.org/entry/601665 601665]]. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.<ref>PMID:12213871</ref>
[https://www.uniprot.org/uniprot/AGRP_HUMAN AGRP_HUMAN] Genetic variations in AGRP may be a cause of obesity (OBESITY) [MIM:[https://omim.org/entry/601665 601665]. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.<ref>PMID:12213871</ref>  
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/AGRP_HUMAN AGRP_HUMAN]] Plays a role in weight homeostasis. Involved in the control of feeding behavior through the central melanocortin system. Acts as alpha melanocyte-stimulating hormone antagonist by inhibiting cAMP production mediated by stimulation of melanocortin receptors within the hypothalamus and adrenal gland. Has very low activity with MC5R (By similarity). Is an inverse agonist for MC3R and MC4R being able to suppress their constitutive activity. It promotes MC3R and MC4R endocytosis in an arrestin-dependent manner.<ref>PMID:9892020</ref> <ref>PMID:11145747</ref> <ref>PMID:17041250</ref> <ref>PMID:10371151</ref> <ref>PMID:15927146</ref>
[https://www.uniprot.org/uniprot/AGRP_HUMAN AGRP_HUMAN] Plays a role in weight homeostasis. Involved in the control of feeding behavior through the central melanocortin system. Acts as alpha melanocyte-stimulating hormone antagonist by inhibiting cAMP production mediated by stimulation of melanocortin receptors within the hypothalamus and adrenal gland. Has very low activity with MC5R (By similarity). Is an inverse agonist for MC3R and MC4R being able to suppress their constitutive activity. It promotes MC3R and MC4R endocytosis in an arrestin-dependent manner.<ref>PMID:9892020</ref> <ref>PMID:11145747</ref> <ref>PMID:17041250</ref> <ref>PMID:10371151</ref> <ref>PMID:15927146</ref>  
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
Check<jmol>
   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/mr/1mr0_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/mr/1mr0_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
   </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1mr0 ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The 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. The NMR structure of this active domain was recently determined and suggested that melanocortin receptor contacts were made primarily by two loops 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 studies of a 34-residue AGRP analogue designed to contain only the cystine knot domain. The designed miniprotein folds 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-like activity of this molecule supports the hypothesis that indeed the cystine knot region possesses the melanocortin 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. and may also find use as a new reagent for probing melanocortin receptor structure and function.
Design, pharmacology, and NMR structure of a minimized cystine knot with agouti-related protein activity.,Jackson PJ, McNulty JC, Yang YK, Thompson DA, Chai B, Gantz I, Barsh GS, Millhauser GL Biochemistry. 2002 Jun 18;41(24):7565-72. PMID:12056887<ref>PMID:12056887</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1mr0" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Barsh, G S]]
[[Category: Homo sapiens]]
[[Category: Chai, B]]
[[Category: Large Structures]]
[[Category: Gantz, I]]
[[Category: Barsh GS]]
[[Category: Jackson, P J]]
[[Category: Chai B]]
[[Category: Mcnulty, J C]]
[[Category: Gantz I]]
[[Category: Millhauser, G M]]
[[Category: Jackson PJ]]
[[Category: Thompson, D A]]
[[Category: Mcnulty JC]]
[[Category: Yang, Y K]]
[[Category: Millhauser GM]]
[[Category: Agouti-related protein]]
[[Category: Thompson DA]]
[[Category: Agrp]]
[[Category: Yang YK]]
[[Category: Ick]]
[[Category: Inhibitor cystine knot]]
[[Category: Melanocortin]]
[[Category: Rational protein design]]
[[Category: Signaling protein]]

Latest revision as of 11:40, 10 April 2024

SOLUTION NMR STRUCTURE OF AGRP(87-120; C105A)SOLUTION NMR STRUCTURE OF AGRP(87-120; C105A)

Structural highlights

1mr0 is a 1 chain structure with sequence from Homo sapiens. This structure supersedes the now removed PDB entry 1mc6. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

AGRP_HUMAN Genetic variations in AGRP may be a cause of obesity (OBESITY) [MIM:601665. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.[1]

Function

AGRP_HUMAN Plays a role in weight homeostasis. Involved in the control of feeding behavior through the central melanocortin system. Acts as alpha melanocyte-stimulating hormone antagonist by inhibiting cAMP production mediated by stimulation of melanocortin receptors within the hypothalamus and adrenal gland. Has very low activity with MC5R (By similarity). Is an inverse agonist for MC3R and MC4R being able to suppress their constitutive activity. It promotes MC3R and MC4R endocytosis in an arrestin-dependent manner.[2] [3] [4] [5] [6]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

  1. ↑ Argyropoulos G, Rankinen T, Neufeld DR, Rice T, Province MA, Leon AS, Skinner JS, Wilmore JH, Rao DC, Bouchard C. A polymorphism in the human agouti-related protein is associated with late-onset obesity. J Clin Endocrinol Metab. 2002 Sep;87(9):4198-202. PMID:12213871
  2. ↑ Yang YK, Thompson DA, Dickinson CJ, Wilken J, Barsh GS, Kent SB, Gantz I. Characterization of Agouti-related protein binding to melanocortin receptors. Mol Endocrinol. 1999 Jan;13(1):148-55. PMID:9892020
  3. ↑ Nijenhuis WA, Oosterom J, Adan RA. AgRP(83-132) acts as an inverse agonist on the human-melanocortin-4 receptor. Mol Endocrinol. 2001 Jan;15(1):164-71. PMID:11145747
  4. ↑ Breit A, Wolff K, Kalwa H, Jarry H, Buch T, Gudermann T. The natural inverse agonist agouti-related protein induces arrestin-mediated endocytosis of melanocortin-3 and -4 receptors. J Biol Chem. 2006 Dec 8;281(49):37447-56. Epub 2006 Oct 14. PMID:17041250 doi:10.1074/jbc.M605982200
  5. ↑ Bolin KA, Anderson DJ, Trulson JA, Thompson DA, Wilken J, Kent SB, Gantz I, Millhauser GL. NMR structure of a minimized human agouti related protein prepared by total chemical synthesis. FEBS Lett. 1999 May 21;451(2):125-31. PMID:10371151
  6. ↑ de Rijke CE, Jackson PJ, Garner KM, van Rozen RJ, Douglas NR, Kas MJ, Millhauser GL, Adan RA. Functional analysis of the Ala67Thr polymorphism in agouti related protein associated with anorexia nervosa and leanness. Biochem Pharmacol. 2005 Jul 15;70(2):308-16. PMID:15927146 doi:10.1016/j.bcp.2005.04.033
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