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Titolo:
BINDING OF NATIVE KAPPA-NEUROTOXINS AND SITE-DIRECTED MUTANTS TO NICOTINIC ACETYLCHOLINE-RECEPTORS
Autore:
CHIAPPINELLI VA; WEAVER WR; MCLANE KE; CONTIFINE BM; FIORDALISI JJ; GRANT GA;
Indirizzi:
ST LOUIS UNIV,SCH MED,DEPT PHARMACOL & PHYSIOL SCI ST LOUIS MO 63104 UNIV MINNESOTA,DEPT CHEM & BIOCHEM DULUTH MN 55812 UNIV MINNESOTA,DEPT MOL BIOL DULUTH MN 55812 UNIV MINNESOTA,DEPT BIOCHEM & BIOPHYS ST PAUL MN 55108 UNIV N CAROLINA,DEPT BIOCHEM & BIOPHYS CHAPEL HILL NC 27599 WASHINGTON UNIV,SCH MED,DEPT MOL BIOL & PHARMACOL ST LOUIS MO 63110 WASHINGTON UNIV,SCH MED,DEPT MED ST LOUIS MO 63110
Titolo Testata:
Toxicon
fascicolo: 11-12, volume: 34, anno: 1996,
pagine: 1243 - 1256
SICI:
0041-0101(1996)34:11-12<1243:BONKAS>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
AMINO-ACID SEQUENCE; NEURONAL BUNGAROTOXIN; CHOLINERGIC RECEPTOR; FUNCTIONAL EXPRESSION; SNAKE NEUROTOXIN; K-BUNGAROTOXIN; ALPHA-SUBUNIT; BRAIN; FLAVITOXIN; PROBE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
42
Recensione:
Indirizzi per estratti:
Citazione:
V.A. Chiappinelli et al., "BINDING OF NATIVE KAPPA-NEUROTOXINS AND SITE-DIRECTED MUTANTS TO NICOTINIC ACETYLCHOLINE-RECEPTORS", Toxicon, 34(11-12), 1996, pp. 1243-1256

Abstract

The kappa-neurotoxins are useful ligands for the pharmacological characterization of nicotinic acetylcholine receptors because they are potent antagonists at only a subgroup of these receptors containing either alpha 3- or alpha 4-subunits (IC (50) less than or equal to 100 nM). Four of these highly homologous, 66 amino acid peptides have been purified from the venom of Bungarus multicinctus [kappa-bungarotoxin (kappa-Bgt), kappa 2-Bgt, kappa 3-Bgt] and Bungarus flaviceps [kappa-flavitoxin (kappa-Fvt)]. Two approaches were taken to examine the binding of these toxins to nicotinic receptors. First, venom-derived kappa-Fvt and kappa-Bgt were radioiodinated and the specific binding was measured of these toxins to overlapping synthetic peptides (16-20 amino acidsin length) prepared based on the known sequence of the nicotinic receptor alpha 3-subunit. At least two main regions of interaction betweenthe toxins and the receptor subunit were identified, both lying in the N-terminal region of the subunit that is exposed to the extracellular space. The second approach examined the importance of several sequence positions in kappa-Bgt for binding to alpha 3-containing receptors in autonomic ganglia and alpha 1-containing muscle receptors. This wasdone using site-directed mutants of kappa-Bgt produced by an Escherichia coli expression system. Arg-34 and position 36 were important for binding to both receptor subtypes, while replacing Gin-26 with Trp-26 (an invariant in alpha-neurotoxins) increased affinity for the muscle receptor by 8-fold. The results confirm that kappa-neurotoxins bind potently to the alpha 3-subunit and bind with considerably reduced affinity (K-d approximate to 10 mu M) to muscle receptors. Site-directed mutagenesis of recombinant kappa-Bgt is thus an important approach for the study of structure-function relationships between kappa-Bgt and nicotinic receptors.

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Documento generato il 27/09/20 alle ore 19:38:40