1qs3: Difference between revisions

Revision as of 15:43, 21 February 2008

NMR SOLUTION CONFORMATION OF AN ANTITOXIC ANALOG OF ALPHA-CONOTOXIN GI

OverviewOverview

The three-dimensional solution conformation of an 11-residue antitoxic analogue of alpha-conotoxin GI, des-Glu1-[Cys3Ala]-des-Cys13-conotoxin GI (CANPACGRHYS-NH(2), designated "GI-15" henceforth), has been determined using two-dimensional (1)H NMR spectroscopy. The disulfide loop region (1C-6C) and the C-terminal tail (8R-11S) are connected by a flexible hinge formed near 7G, and the pairwise backbone rmsds for the former and the latter are 0.58 and 0.65 A, respectively. Superpositioning GI-15 with the structure of alpha-conotoxin GI shows that the two share an essentially identical fold in the common first disulfide loop region (1C-6C). However, the absence of the second disulfide loop in GI-15 results in segmental motion of the C-terminal half, causing the key receptor subtype selectivity residue 8R (Arg9 in alpha-conotoxin GI) to lose its native spatial orientation. The combined features of structural equivalence in the disulfide loop and a mobile C-terminal tail appear to be responsible for the activity of GI-15 as a competitive antagonist against native toxin. Electrostatic surface potential comparisons of the first disulfide region of GI-15 with other alpha-conotoxins or receptor-bound states of acetylcholine and d-tubocurarine show a common protruding surface that may serve as the minimal binding determinant for the neuromuscular acetylcholine receptor alpha 1-subunit. On the basis of the original "Conus toxin macrosite model" [Olivera, B. M., Rivier, J., Scott, J. K., Hillyard, D. R., and Cruz, L. J. (1991) J. Biol. Chem. 266, 1923-1936], we propose a revised binding model which incorporates these results.

About this StructureAbout this Structure

1QS3 is a Single protein structure of sequence from [1] with as ligand. Full crystallographic information is available from OCA.

ReferenceReference

NMR solution conformation of an antitoxic analogue of alpha-conotoxin GI: identification of a common nicotinic acetylcholine receptor alpha 1-subunit binding surface for small ligands and alpha-conotoxins., Mok KH, Han KH, Biochemistry. 1999 Sep 14;38(37):11895-904. PMID:10508392

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 caption="1qs3" />
 '''NMR SOLUTION CONFORMATION OF AN ANTITOXIC ANALOG OF ALPHA-CONOTOXIN GI'''<br />
 ==Overview==
-The three-dimensional solution conformation of an 11-residue antitoxic, analogue of alpha-conotoxin GI, des-Glu1-[Cys3Ala]-des-Cys13-conotoxin GI, (CANPACGRHYS-NH(2), designated "GI-15" henceforth), has been determined, using two-dimensional (1)H NMR spectroscopy. The disulfide loop region, (1C-6C) and the C-terminal tail (8R-11S) are connected by a flexible hinge, formed near 7G, and the pairwise backbone rmsds for the former and the, latter are 0.58 and 0.65 A, respectively. Superpositioning GI-15 with the, structure of alpha-conotoxin GI shows that the two share an essentially, identical fold in the common first disulfide loop region (1C-6C). However, the absence of the second disulfide loop in GI-15 results in segmental, motion of the C-terminal half, causing the key receptor subtype, selectivity residue 8R (Arg9 in alpha-conotoxin GI) to lose its native, spatial orientation. The combined features of structural equivalence in, the disulfide loop and a mobile C-terminal tail appear to be responsible, for the activity of GI-15 as a competitive antagonist against native, toxin. Electrostatic surface potential comparisons of the first disulfide, region of GI-15 with other alpha-conotoxins or receptor-bound states of, acetylcholine and d-tubocurarine show a common protruding surface that may, serve as the minimal binding determinant for the neuromuscular, acetylcholine receptor alpha 1-subunit. On the basis of the original, "Conus toxin macrosite model" [Olivera, B. M., Rivier, J., Scott, J. K., Hillyard, D. R., and Cruz, L. J. (1991) J. Biol. Chem. 266, 1923-1936], we, propose a revised binding model which incorporates these results.
+The three-dimensional solution conformation of an 11-residue antitoxic analogue of alpha-conotoxin GI, des-Glu1-[Cys3Ala]-des-Cys13-conotoxin GI (CANPACGRHYS-NH(2), designated "GI-15" henceforth), has been determined using two-dimensional (1)H NMR spectroscopy. The disulfide loop region (1C-6C) and the C-terminal tail (8R-11S) are connected by a flexible hinge formed near 7G, and the pairwise backbone rmsds for the former and the latter are 0.58 and 0.65 A, respectively. Superpositioning GI-15 with the structure of alpha-conotoxin GI shows that the two share an essentially identical fold in the common first disulfide loop region (1C-6C). However, the absence of the second disulfide loop in GI-15 results in segmental motion of the C-terminal half, causing the key receptor subtype selectivity residue 8R (Arg9 in alpha-conotoxin GI) to lose its native spatial orientation. The combined features of structural equivalence in the disulfide loop and a mobile C-terminal tail appear to be responsible for the activity of GI-15 as a competitive antagonist against native toxin. Electrostatic surface potential comparisons of the first disulfide region of GI-15 with other alpha-conotoxins or receptor-bound states of acetylcholine and d-tubocurarine show a common protruding surface that may serve as the minimal binding determinant for the neuromuscular acetylcholine receptor alpha 1-subunit. On the basis of the original "Conus toxin macrosite model" [Olivera, B. M., Rivier, J., Scott, J. K., Hillyard, D. R., and Cruz, L. J. (1991) J. Biol. Chem. 266, 1923-1936], we propose a revised binding model which incorporates these results.
 ==About this Structure==
-QS3 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ] with NH2 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1QS3 OCA].
+QS3 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ] with <scene name='pdbligand=NH2:'>NH2</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1QS3 OCA].
 ==Reference==
 NMR solution conformation of an antitoxic analogue of alpha-conotoxin GI: identification of a common nicotinic acetylcholine receptor alpha 1-subunit binding surface for small ligands and alpha-conotoxins., Mok KH, Han KH, Biochemistry. 1999 Sep 14;38(37):11895-904. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10508392 10508392]
 [[Category: Single protein]]
-[[Category: Han, K.H.]]
+[[Category: Han, K H.]]
-[[Category: Mok, K.H.]]
+[[Category: Mok, K H.]]
 [[Category: NH2]]
 [[Category: antitoxic analog]]
@@ Line 19: / Line 19: @@
 [[Category: nicotinic acetylcholine receptor]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 00:56:10 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:43:08 2008''