Interacting surfaces of neurotoxins and acetylcholine receptor

Tsetlin, Victor I.; Karlsson, Evert; Utkin, Yuri N.; Pluzhnikov, Kirill A.; Arseniev, Alexander S.; Surin, A.M.; Kondakov, V.V.; Bystrov, V. F.; Иванов, В. Т.; Ovchinnikov, Yu.A.

doi:10.1016/0041-0101(82)90171-4

Cited by 58 publications

(24 citation statements)

References 20 publications

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“…5). That salt linkage between charged Arg33 and Asp3 residues, which appeared compatible [22] with the Eb electron-density map at lower resolution, is now absent. There is one hydrogen bond between Asp31 carboxyl oxygen and ArgJ3 amide nitrogen and six Asp-Arg van der Waal's interactions.…”

Section: Residue Clusters and The Hydrophobic 'Trp' Cleftmentioning

confidence: 82%

“…Binding interactions between AChR and LysZ7 have been demonstrated in the short-chain toxins by studies of mono derivatives, and the functional role of LysZ7 has thus been established. toxins when Lys27 is chemically modified, close contact of Lysz7 with receptor surface is still maintained, as biophysical studies using both ESR and fluorescent techniques [20,22,41, 421 have shown. The role of Pro44 is, by implication, functional since it forms part of the 'Trp' cleft wall.…”

Section: Residue Clusters and The Hydrophobic 'Trp' Cleftmentioning

confidence: 99%

“…Furthermore in neurotoxin I1 ( N . n. oxiana) binding by both Lys(K27) and Lys(K53) residues was found to occur in the vicinity of one or more AChR Trp residues [22].…”

Section: Residue Clusters and The Hydrophobic 'Trp' Cleftmentioning

confidence: 99%

“…There is one hydrogen bond between Asp31 carboxyl oxygen and ArgJ3 amide nitrogen and six Asp-Arg van der Waal's interactions. The long Arg33(K37) side-chain is mobile; thus, if these two residues are an acetylcholinemimetic pair, as suggested [2], the appropriate stereochemical disposition could be adopted, whatever that may ultimately be shown to be [46, The type-conserved K33 residue, usually His, is, in Eb, completely isolated from the rest of the neurotoxin I1 (N. n. oxiunu) suggests close contact with receptor [22]. Topographically, when the concave toxin-binding surface is inverted (consider Fig.…”

Section: Residue Clusters and The Hydrophobic 'Trp' Cleftmentioning

confidence: 99%

“…Other shortchain toxin I and T-C residues shown are Am5, His', Gln', Sera, Ser', Pro", Thr13 and, also Gin" and Lys". reactive-site residues in two short-chain toxins, have been successfully correlated with those in the Eb 0.25-nm resolution structure [21]; Proton and 19F NMR studies of two labelled long-chain toxins suggest that their pH-averaged conformation is of the short-chain toxin type [22]. In addition, the a-cobratoxin structure, determined by X-ray crystal structure analysis at 0.28 nm resolution [23], provides a description of a long-chain reactive site stereochemistry which does not differ significantly from the Eb model.…”

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confidence: 99%

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Erabutoxin b

Low

Corfield

1986

European Journal of Biochemistry

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A study has been made, following high-resolution refinement at 0.14 nm, of the structure of erabutoxin b, prototype postsynaptic neurotoxin from snake venom. The detailed patterns of intramolecular van der Waal's interactions have been determined. From information, hitherto unavailable, about atomic temperature parameters, the relative mobilities in different regions of the molecule have been estimated. A detailed model of structure/function relationships in these neurotoxins, whch bind to the acetylcholine receptor, has thus been established: the probable dynamic mode of toxin-receptor binding is described. The model identifies, and the binding mode depends on a unique structural feature of these protein toxins: the hydrophobic 'Trp' cleft. Chargecharge interactions are implicated in initial toxin orientation on the receptor surface. Possible reactive-site extension in short-chain toxins is described. Modifications in binding mode of long-chain toxins are considered. The relative mobilities of antigenic site residues are discussed.The postsynaptic neurotoxins from snake venom have been widely employed as probes of nicotinic acetylcholine receptor (AChR) function. Determination of the three-dimensional structure [l] of one of these protein toxins, erabutoxin b (Eb), led to early identification and characterization of the toxin reactive site [l -31, that interactive surface domain which binds to the receptor. Subsequent high-resolution refinement at 0.14 nm of this toxin structure [4] provides a more detailed picture and clearer understanding of the probable stereochemical aspects and dynamic features of toxin-receptor binding interactions.These neurotoxins bind to receptor competitively with acetylcholine (ACh) [5]. They produce a non-depolarising neuromuscular block. Extensive sequence homologies [2,6,7] in this large class of small single-chain proteins are expressed not only in the numbers of invariant (I) and type-conserved (T-C) residues, but also by their distribution along invariant length segments of peptide chain. The homologies link both series of toxins: short-chain, with 60-62 residues and four invariant disulfide bridges, and long-chain with, usually, 71 -74 residues and a fifth additional disulfide bridge. Initial characterization [2] of the toxin reactive site was therefore based on consideration of the stereochemical distribution of conserved residues as found in the prototype erabutoxin bCorrespondence to B. W. Low,

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Section: Residue Clusters and The Hydrophobic 'Trp' Cleftmentioning

confidence: 82%

Section: Residue Clusters and The Hydrophobic 'Trp' Cleftmentioning

confidence: 99%

“…Furthermore in neurotoxin I1 ( N . n. oxiana) binding by both Lys(K27) and Lys(K53) residues was found to occur in the vicinity of one or more AChR Trp residues [22].…”

Section: Residue Clusters and The Hydrophobic 'Trp' Cleftmentioning

confidence: 99%

Section: Residue Clusters and The Hydrophobic 'Trp' Cleftmentioning

confidence: 99%

mentioning

confidence: 99%

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Erabutoxin b

Low

Corfield

1986

European Journal of Biochemistry

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Biochemische Aspekte der cholinergen Reizung

Maelicke

1984

Angewandte Chemie

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Lebende Organismen kbnnen sich nur entwickeln und erhalten, solange eine wirksame Kommunikation zwischen ihren Einzelkomponentenden Zellenbesteht. Diese interzellullre Kommunikation ist hauptsachlich chemischer Natur: Sie benutzt als Botenstoffe Neurotransmitter und Hormone und als Signalempfanger Rezeptoren. Die Konzentrationen aller beteiligten Komponenten sind gewbhnlich gering. Ausnahmen gibt es bei einigen synaptischen Kommunikationssystemen wie der Nerven-Muskel-Synapse oder ihrer speziellen Form, der Nerven-Elektrozyt-Synapse in den elektrischen Organen von Zitteraal (Electrophorus) und Zitterrochen (Torpedo). Diese Systeme sind der biochemischen Analyse gut zuganglich, so daD sie sich zur Aufkliirung der molekularen Grundlagen derartiger biologischer Kommunikationsprozesse eignen. Auf diese Weise ist gefunden worden, daI3 der nicotinische Acetylcholinrezeptor der Muskelzelle nicht nur das von der zugeh6rigen Nervenzelle ausgesendete Signal empfangt, sondern dieses auch selbst in eine elektrische Aktivitilt der Muskelzelle umsetzt. Fluoreszenzkinetische Untersuchungen der Wechselwirkung des Acetylcholinrezeptors nit seinen Liganden haben zu einem neuen Model1 des molekularen Mechanismus der cholinergen Reizung gefiihrt, das auch von physiologischen und immunologischen Befunden gestiitzt wird. Angew. Chem. 96 (1984) 193-219 @ Verlag Chemie GmbH. 0-6940 Weinheim. 1984 0014-8249/84/0303-0193 S 02.50/0 193 Acetylcholin J 2 prasynaptisch Verpackung in Vesikeln enzymatische Acetylierung t Wiederaufnahme von Cholin-50 ms Abb. 2. Acetylcholin-induzierte hderungen der elektrischcn Lcitfahigkeit einzelncr loncnkanalc des Acetylcholinrezeptor. a) Nach Hami// et al. [33] wurde ein McmbranstUckchen eines embryonalcn Rattenmuskels so an der McDpipettc festgcsaugt, daD ein Ubergangswiderstand von einigen Gn erreicht wurdc. Unter Bedingungen der Spannungsklemme (die Spannung Uber der Membran wird wahrcnd dcr gcsamten Mcssung konstant gehalten) werden dann die jlnderungen des Stromflusses aufgezeichnet. Diese sind den iinderungen dcr Mcmbranleitf3higkeit dirckt proportional. Eine derartige Anordnung wird als patch-clamp bezeichnct. Pipettenl6sungen: innen 150 m~ KCI, 1 mM EGTA, 4 mM HEPES, pH 7.2; auDen 150 mM NaCI. 2 mM CaCI2, 2 mM MgCh. 4 mM KCI, 4~ HEPES, pH 7.2. Das Membranpotential wurde auf -70 mV festgelcgt, was einer lcichtcn Hyperpolarisation dcr Muskelmcmbran entspricht. MeBtemperatur ca. 2 5 T .b) Die Strom-&it-Kurve wurdc nach Zugabc von Acetylcholin (2 pM) zur AuDenl6sung aufgcnommen. Wic aus den Amplituden zu erkcnnen ist, traten neben Einzelkanalereignissen auch Doppcl-und Drcifachkanalereignisse auf (gleichzeitige Aktivierung von zwei bzw. drei Rezeptorkan~len). Die Messung wurde von Dr. C. Merhfessel, Univcritit Bochum, durchgefiihrt. Angew. Chem. 96 (1984) 193-219 4 a , X = B r , 4b. X = CnH2,,+, , 4 c , X = ( C H .~-, -N H~) -N O~

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Biochemical Aspects of Cholinergic Excitation

Maelicke

1984

Angew. Chem. Int. Ed. Engl.

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A prerequisite for every biological system to develop and to continue to function ("to live") is an effective communication between its components, i.e. its cells. This intercellular communication is essentially of a chemical nature: It employs neurotransmitters and hormones as messengers, and receptors as the receivers of transmitted signals. As is typical for all communication systems, biological signal processes usually also utilize only relatively small amounts of material. This general rule, however, does not apply to some synaptic communication systems. One typical exception, for instance, is the nerve-muscle synapse and, in particular, its special form, the nerve-electroplaque synapse of electric fish. These systems, therefore, lend themselves to biochemical studies permitting investigation of the molecular basis of biological communication processes. Thus, the acetylcholine receptor of the plasma membrane of the postsynaptic cell was established as a structurally and functionally rather complicated "transducer system" responsible for both the reception of the chemical message and its conversion into an electrical activity of the receiving cell.

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Interacting surfaces of neurotoxins and acetylcholine receptor

Cited by 58 publications

References 20 publications

Erabutoxin b

Erabutoxin b

Biochemische Aspekte der cholinergen Reizung

Biochemical Aspects of Cholinergic Excitation

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