1pjv
From Proteopedia
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| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1pjv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pjv OCA], [http://www.ebi.ac.uk/pdbsum/1pjv PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1pjv RCSB]</span> | ||
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[[Category: scorpion toxin]] | [[Category: scorpion toxin]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 23:00:42 2008'' |
Revision as of 20:00, 30 March 2008
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Cobatoxin 1 from Centruroides noxius Scorpion venom: Chemical Synthesis, 3-D Structure in Solution, Pharmacology and Docking on K+ channels
Overview
CoTX1 (cobatoxin 1) is a 32-residue toxin with three disulphide bridges that has been isolated from the venom of the Mexican scorpion Centruroides noxius Hoffmann. Here we report the chemical synthesis, disulphide bridge organization, 3-D (three-dimensional) solution structure determination, pharmacology on K+ channel subtypes (voltage-gated and Ca2+-activated) and docking-simulation experiments. An enzyme-based cleavage of the synthetic folded/oxidized CoTX1 indicated half-cystine pairs between Cys3-Cys22, Cys8-Cys27 and Cys12-Cys29. The 3-D structure of CoTX1 (solved by 1H-NMR) showed that it folds according to the common alpha/beta scaffold of scorpion toxins. In vivo, CoTX1 was lethal after intracerebroventricular injection to mice (LD50 value of 0.5 microg/mouse). In vitro, CoTX1 tested on cells expressing various voltage-gated or Ca2+-activated (IKCa1) K+ channels showed potent inhibition of currents from rat K(v)1.2 ( K(d) value of 27 nM). CoTX1 also weakly competed with 125I-labelled apamin for binding to SKCa channels (small-conductance Ca2+-activated K+ channels) on rat brain synaptosomes (IC50 value of 7.2 microM). The 3-D structure of CoTX1 was used in docking experiments which suggests a key role of Arg6 or Lys10, Arg14, Arg18, Lys21 (dyad), Ile23, Asn24, Lys28 and Tyr30 (dyad) residues of CoTX1 in its interaction with the rat K(v)1.2 channel. In addition, a [Pro7,Gln9]-CoTX1 analogue (ACoTX1) was synthesized. The two residue replacements were selected aiming to restore the RPCQ motif in order to increase peptide affinity towards SKCa channels, and to alter the CoTX1 dipole moment such that it is expected to decrease peptide activity on K(v) channels. Unexpectedly, ACoTX1 exhibited an activity similar to that of CoTX1 towards SKCa channels, while it was markedly more potent on IKCa1 and several voltage-gated K+ channels.
About this Structure
1PJV is a Single protein structure of sequence from [1]. Full crystallographic information is available from OCA.
Reference
Cobatoxin 1 from Centruroides noxius scorpion venom: chemical synthesis, three-dimensional structure in solution, pharmacology and docking on K+ channels., Jouirou B, Mosbah A, Visan V, Grissmer S, M'Barek S, Fajloun Z, Van Rietschoten J, Devaux C, Rochat H, Lippens G, El Ayeb M, De Waard M, Mabrouk K, Sabatier JM, Biochem J. 2004 Jan 1;377(Pt 1):37-49. PMID:14498829
Page seeded by OCA on Sun Mar 30 23:00:42 2008
Categories: Single protein | Ayeb, M El. | Grissmer, S. | Jouirou, B. | Mabrouk, K. | Mosbah, A. | Rochat, H. | Sabatier, J M. | Visan, V. | Waard, M De. | 1h-nmr spectroscopy | 3-d structure | Centuroides noxius | Chemical synthesis | Circular dichroism | Cobatoxin 1 | Docking experiment | K+ channel | Molecular modeling | Scorpion toxin
