Sandbox 174: Difference between revisions
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=General Structure= | =General Structure= | ||
[[Image: | [[Image:figurename.png|thumb|Overall structure of Alpha-Bungarotoxin, with all individual residues visible]] | ||
A large amount of highly homologous snake neurotoxins have been sequenced (>60), and can be grouped into two major classes. Short neurotoxins are between 60-62 amino acids long, and consist of four disulphide bonds, and long neurotoxins - which α-BGT falls under - are between 71-74 amino acids long and contain five <scene name='Sandbox_174/Disulphides/2'>Disulphide Bonds</scene> per subunit. α-BGT contains 74 amino acids, and is one of the major components of ''Bungarus multicuntus'' venom. Chemical modifications of individual residues has shown that no single amino acid is mandatory for binding, signifying the significance of structure, rather than sequence, and the concept of multicontact interaction with the acetylcholine receptor <ref> Karlsson, E. (1979) in Lee,C Y (ed), ''Handbook of Experimental Pharmacology'' Springer-Verlag, Berlin Vol 52, pp 159-212;Low, B.W. (1979) In Lee,c Y (ed). ''Handbook of Experimental Pharmacology'' Springer-Verlag, Berlin, Vol 52, pp 213-257.</ref>. The importance of structure in binding has been tested by Love & Stroud (1986)<ref name="main">Love, A.R. and Stroud, R.M. (1986) The Crystal Structure of α-Bungarotoxin at 2.5 Å resolution: Relation to Solution Structure and Binding to Acetylcholine Receptor. ''Protein Eng'' '''1''', 37-46. </ref> by determining whether the homology and common mode of action of neurotoxins is facilitated by the three-dimensional structure. Using X-ray crystallography at various resolutions, neurotoxins erabutoxin and cobratoxin were compared to that of α-BGT to determine the level of three-dimensional similarity. | A large amount of highly homologous snake neurotoxins have been sequenced (>60), and can be grouped into two major classes. Short neurotoxins are between 60-62 amino acids long, and consist of four disulphide bonds, and long neurotoxins - which α-BGT falls under - are between 71-74 amino acids long and contain five <scene name='Sandbox_174/Disulphides/2'>Disulphide Bonds</scene> per subunit. α-BGT contains 74 amino acids, and is one of the major components of ''Bungarus multicuntus'' venom. Chemical modifications of individual residues has shown that no single amino acid is mandatory for binding, signifying the significance of structure, rather than sequence, and the concept of multicontact interaction with the acetylcholine receptor <ref> Karlsson, E. (1979) in Lee,C Y (ed), ''Handbook of Experimental Pharmacology'' Springer-Verlag, Berlin Vol 52, pp 159-212;Low, B.W. (1979) In Lee,c Y (ed). ''Handbook of Experimental Pharmacology'' Springer-Verlag, Berlin, Vol 52, pp 213-257.</ref>. The importance of structure in binding has been tested by Love & Stroud (1986)<ref name="main">Love, A.R. and Stroud, R.M. (1986) The Crystal Structure of α-Bungarotoxin at 2.5 Å resolution: Relation to Solution Structure and Binding to Acetylcholine Receptor. ''Protein Eng'' '''1''', 37-46. </ref> by determining whether the homology and common mode of action of neurotoxins is facilitated by the three-dimensional structure. Using X-ray crystallography at various resolutions, neurotoxins erabutoxin and cobratoxin were compared to that of α-BGT to determine the level of three-dimensional similarity. | ||
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Elapidae neurotoxins bind specifically and tightly (with a very high affinity) in a non-covalent manner to the nicotinic acetylcholine receptors in cholinergic synapses of their victims. This prevents normal neurotransmitter-induced channel opening, which in turn blocks postsynaptic membrane depolarization<ref name="main">Love, A.R. and Stroud, R.M. (1986) The Crystal Structure of α-Bungarotoxin at 2.5 Å resolution: Relation to Solution Structure and Binding to Acetylcholine Receptor. ''Protein Eng'' '''1''', 37-46.</ref>, classifying the molecule as a postsynaptic neurotoxin. | Elapidae neurotoxins bind specifically and tightly (with a very high affinity) in a non-covalent manner to the nicotinic acetylcholine receptors in cholinergic synapses of their victims. This prevents normal neurotransmitter-induced channel opening, which in turn blocks postsynaptic membrane depolarization<ref name="main">Love, A.R. and Stroud, R.M. (1986) The Crystal Structure of α-Bungarotoxin at 2.5 Å resolution: Relation to Solution Structure and Binding to Acetylcholine Receptor. ''Protein Eng'' '''1''', 37-46.</ref>, classifying the molecule as a postsynaptic neurotoxin. | ||
==neuromuscular acetylcholine receptor binding== | ==neuromuscular acetylcholine receptor binding== | ||
The | The irriversible and competitive binding to the acetylcholine receptor by α-BTG can be devastating to an organisms health due to its ability to block the receptors activity. | ||
http://www.ncbi.nlm.nih.gov/pubmed/12885641 | http://www.ncbi.nlm.nih.gov/pubmed/12885641 | ||
==α7 nicotinic acetylcholine receptor binding== | ==α7 nicotinic acetylcholine receptor binding== | ||
Response to sensory stimuli and seizure genesis has been linked to nicotinic mechanisms<ref>Freedman, R. Wetmore, C. Stromberg, I. Leonard, S. Olsona, L. (1993) Alpha-Bungarotoxin Binding to Hippocampal Interneurons: lmmunocytochemical Characterization and Effects on Growth Factor Expression. ''Journal of Neuroscience'' 13:1965-1975. </ref>, which are mediated by two major classes of receptors: Ganglionic type, and neuromuscular type, which pharmacological analysis of seizure genesis and habituation in the rat brain is thought to be mediated by the latter type <ref> Miner L.L. Collins A.C. (1989) Strain comparison of nicotine-induced seizure sensitivity and nicotinic receptors. ''Pharmacol Biochem Behav'' '''33''', 469-475;Luntz-Leybman, V. Bickford, P. Freedman, R. (1992) Cholinergic gating of response to auditory stimuli in rat hippocampus. ''Brain Res'' '''587''', 130-l-36.</ref>. α-BGT demonstrates this relationship due to its prominent binding in the CA3 region of the hippocampus <ref> Hunt, S.P. Schmidt, J. (1978) The electron microscopic autoradiographic localization of alpha-bungarotoxin binding sites within the central nervous system of the rat: ''Brain Res'' '''142''', 152-l 59;Segal, M. Dudai, Y. Amsterdam, A. (1978) Distribution of cu-bungarotoxin- | |||
binding cholinergic nicotinic receptor in rat brain. ''Brain Res'' '''148''', 105-l 19.</ref>. | binding cholinergic nicotinic receptor in rat brain. ''Brain Res'' '''148''', 105-l 19.</ref>. | ||
