1mr0
From Proteopedia
(New page: 200px<br /> <applet load="1mr0" size="450" color="white" frame="true" align="right" spinBox="true" caption="1mr0" /> '''SOLUTION NMR STRUCTURE OF AGRP(87-120; C105...) |
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'''SOLUTION NMR STRUCTURE OF AGRP(87-120; C105A)'''<br /> | '''SOLUTION NMR STRUCTURE OF AGRP(87-120; C105A)'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The agouti-related protein (AGRP) is an endogenous antagonist of the | + | 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. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1MR0 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ]. This structure | + | 1MR0 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ]. This structure supersedes the now removed PDB entry 1MC6. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MR0 OCA]. |
==Reference== | ==Reference== | ||
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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12056887 12056887] | 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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12056887 12056887] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Barsh, G | + | [[Category: Barsh, G S.]] |
[[Category: Chai, B.]] | [[Category: Chai, B.]] | ||
[[Category: Gantz, I.]] | [[Category: Gantz, I.]] | ||
| - | [[Category: Jackson, P | + | [[Category: Jackson, P J.]] |
| - | [[Category: Mcnulty, J | + | [[Category: Mcnulty, J C.]] |
| - | [[Category: Millhauser, G | + | [[Category: Millhauser, G M.]] |
| - | [[Category: Thompson, D | + | [[Category: Thompson, D A.]] |
| - | [[Category: Yang, Y | + | [[Category: Yang, Y K.]] |
[[Category: agouti-related protein]] | [[Category: agouti-related protein]] | ||
[[Category: agrp]] | [[Category: agrp]] | ||
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[[Category: rational protein design]] | [[Category: rational protein design]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:58:08 2008'' |
Revision as of 11:58, 21 February 2008
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SOLUTION NMR STRUCTURE OF AGRP(87-120; C105A)
Contents |
Overview
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.
Disease
Known diseases associated with this structure: Leanness, inherited OMIM:[602311], Obesity, late-onset OMIM:[602311]
About this Structure
1MR0 is a Single protein structure of sequence from [1]. This structure supersedes the now removed PDB entry 1MC6. Full crystallographic information is available from OCA.
Reference
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
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