Sandbox 174: Difference between revisions
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==Secondary structure & Disulphide bonds== | ==Secondary structure & Disulphide bonds== | ||
Hydrogen bods present allow for an antiparallel β-sheet, which is the only secondary structure present and acts to keep the second and third loops roughly parallel<ref name="main"></ref>. The three-loop structure is preserved by four invariant disulphide bridges, which are present in all neurotoxins. The fifth disulphide bridge is located at the end of the second loop, and can be reduced without any effect on the binding affinity of the molecule, while a total loss of toxicity is demonstrated when the remaining disulphides are reduced, producing a random coil structure much different than the native conformation<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>. | Hydrogen bods present allow for an antiparallel β-sheet, which is the only secondary structure present and acts to keep the second and third loops roughly parallel<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>. The three-loop structure is preserved by four invariant disulphide bridges, which are present in all neurotoxins. The fifth disulphide bridge is located at the end of the second loop, and can be reduced without any effect on the binding affinity of the molecule, while a total loss of toxicity is demonstrated when the remaining disulphides are reduced, producing a random coil structure much different than the native conformation<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>. | ||
The comination of the multiple disulphide bonds and small amount of secondary structure is the cause for the extreme stability of neurotoxins like α-BGT, providing resistance to denaturing forces such as boiling<ref> Tu, A.T. and Hong, B.S (1971) ''J Biol Chem''. '''246''', 2772-2779;Yang, C.C. ''Toxicon'' '''12''', 1-43.</ref> and strong acids<ref>Chiceportiche, R. Rochat, C. Sampien, F. Lazdunski, M. (1972) ''Biochemistry'' '''14''', 2081-2091;Chen, Y.H. Tai, J.C. Huand, W.J. Lau, M.Z. Hung, M.C. Lai, M.D. Yang, J.T. (1982) ''Biochemistry'' '''21''' 2592-2600</ref>. Functionally important residues contained in the extended loops are preserved by the clustering of disulphides near one end of the α-BGT molecule. This is due to an increased amount of flexibility in these extended loops, which is possibly quite important for interaction with acetylcholine receptors. | The comination of the multiple disulphide bonds and small amount of secondary structure is the cause for the extreme stability of neurotoxins like α-BGT, providing resistance to denaturing forces such as boiling<ref> Tu, A.T. and Hong, B.S (1971) ''J Biol Chem''. '''246''', 2772-2779;Yang, C.C. ''Toxicon'' '''12''', 1-43.</ref> and strong acids<ref>Chiceportiche, R. Rochat, C. Sampien, F. Lazdunski, M. (1972) ''Biochemistry'' '''14''', 2081-2091;Chen, Y.H. Tai, J.C. Huand, W.J. Lau, M.Z. Hung, M.C. Lai, M.D. Yang, J.T. (1982) ''Biochemistry'' '''21''' 2592-2600</ref>. Functionally important residues contained in the extended loops are preserved by the clustering of disulphides near one end of the α-BGT molecule. This is due to an increased amount of flexibility in these extended loops, which is possibly quite important for interaction with acetylcholine receptors. | ||
=Functions= | =Functions= | ||
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. | 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>. | ||
==neuromuscular acetylcholine receptor binding== | ==neuromuscular acetylcholine receptor binding== | ||
==α7 nicotinic acetylcholine receptor binding== | ==α7 nicotinic acetylcholine receptor binding== | ||
Reponse 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 and | Reponse 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>. | |||
