Cross Pharmacological, Biochemical and Computational Studies of a Human Kv3.1b Inhibitor from Androctonus australis Venom
Abstract
:1. Introduction
2. Results
2.1. AahG50 Toxic Venom Fraction of Androctonus australis hector Scorpion Blocks Human Kv3.1 Channel
2.2. Pharmacological Characterization of the Component Inhibiting Kv3.1 Channel
2.2.1. Whole Cell Tests with AahG50 FPLC Fractions
2.2.2. Whole-Cell Tests with HPLC Fractions on IKv3.1
2.3. Validation of H7 Inhibitory Effect on Kv3.1 Single Current Recording
2.4. Mass Spectrometric Analysis of H7
2.5. In Silico Study to Identify the Peptide Blocking Kv3.1
2.5.1. Molecular Models of Alpha-KTx 15.1, AaTXK-Beta and Kv3.1 Channel
2.5.2. Molecular Docking of Alpha-KTx 15.1 and AaTXK-Beta with Kv3.1 Channel
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. Methods
4.2.1. Biochemistry
4.2.2. Electrophysiology
- Two-Microelectrodes Voltage Clamp
- Whole-cell patch-clamp
- Single channel recording
4.2.3. Data and Statistical Analysis
4.2.4. Proteomics
- Protein identification: NanoLC/HRMS-MS:
4.2.5. Computational or In Silico Study
- Molecular modelling of alpha-KTx 15.1, AaTXK-beta and Kv3.1 potassium channel
- Toxin-channel docking study
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Martina, M.; Schultz, J.H.; Ehmke, H.; Monyer, H.; Jonas, P. Functional and Molecular Differences between Voltage-Gated K+ Channels of Fast-Spiking Interneurons and Pyramidal Neurons of Rat Hippocampus. J. Neurosci. 1998, 18, 8111–8125. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Massengill, J.L.; Smith, M.A.; Son, D.I.; O’Dowd, D.K. Differential Expression of K 4-AP Currents and Kv3.1 Potassium Channel Transcripts in Cortical Neurons That Develop Distinct Firing Phenotypes. J. Neurosci. 1997, 17, 3136–3147. [Google Scholar] [CrossRef] [Green Version]
- McDonald, A.J.; Mascagni, F. Differential Expression of Kv3.1b and Kv3.2 Potassium Channel Subunits in Interneurons of the Basolateral Amygdala. Neuroscience 2006, 138, 537–547. [Google Scholar] [CrossRef]
- Perney, T.M.; Marshall, J.; Martin, K.A.; Hockfield, S.; Kaczmarek, L.K. Expression of the MRNAs for the Kv3.1 Potassium Channel Gene in the Adult and Developing Rat Brain. J. Neurophysiol. 1992, 68, 756–766. [Google Scholar] [CrossRef]
- Rudy, B.; McBain, C.J. Kv3 Channels: Voltage-Gated K+ Channels Designed for High-Frequency Repetitive Firing. Trends Neurosci 2001, 24, 517–526. [Google Scholar] [CrossRef]
- Weiser, M.; Vega-Saenz de Miera, E.; Kentros, C.; Moreno, H.; Franzen, L.; Hillman, D.; Baker, H.; Rudy, B. Differential Expression of Shaw-Related K+ Channels in the Rat Central Nervous System. J. Neurosci. 1994, 14, 949–972. [Google Scholar] [CrossRef] [Green Version]
- Espinosa, F.; McMahon, A.; Chan, E.; Wang, S.; Ho, C.S.; Heintz, N.; Joho, R.H. Alcohol Hypersensitivity, Increased Locomotion, and Spontaneous Myoclonus in Mice Lacking the Potassium Channels Kv3.1 and Kv3.3. J. Neurosci. 2001, 21, 6657–6665. [Google Scholar] [CrossRef] [Green Version]
- Espinosa, F.; Marks, G.; Heintz, N.; Joho, R.H. Increased Motor Drive and Sleep Loss in Mice Lacking Kv3-Type Potassium Channels. Genes Brain Behav. 2004, 3, 90–100. [Google Scholar] [CrossRef]
- Liebau, S.; Pröpper, C.; Böckers, T.; Lehmann-Horn, F.; Storch, A.; Grissmer, S.; Wittekindt, O.H. Selective Blockage of Kv1.3 and Kv3.1 Channels Increases Neural Progenitor Cell Proliferation. J. Neurochem. 2006, 99, 426–437. [Google Scholar] [CrossRef] [PubMed]
- Yasuda, T.; Cuny, H.; Adams, D.J. Kv3.1 Channels Stimulate Adult Neural Precursor Cell Proliferation and Neuronal Differentiation: Kv3.1 Channels in Adult Neural Precursor Cells. J. Physiol. 2013, 591, 2579–2591. [Google Scholar] [CrossRef] [PubMed]
- Tabka, H.; Cheikh, A.; Maatoug, S.; Ayeb, M.E.; Bendahhou, S.; Benkhalifa, R. First Evidence of Kv3.1b Potassium Channel Subtype Expression during Neuronal Serotonergic 1C11 Cell Line Development. Int. J. Mol. Sci. 2020, 21, 7175. [Google Scholar] [CrossRef] [PubMed]
- Matsukawa, H.; Wolf, A.M.; Matsushita, S.; Joho, R.H.; Knöpfel, T. Motor Dysfunction and Altered Synaptic Transmission at the Parallel Fiber-Purkinje Cell Synapse in Mice Lacking Potassium Channels Kv3.1 and Kv3.3. J. Neurosci. 2003, 23, 7677–7684. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, S.J.; Kaczmarek, L.K. Aminoglycosides Block the Kv3.1 Potassium Channel and Reduce the Ability of Inferior Colliculus Neurons to Fire at High Frequencies. J. Neurobiol. 2005, 62, 439–452. [Google Scholar] [CrossRef] [PubMed]
- Sung, M.J.; Ahn, H.S.; Hahn, S.J.; Choi, B.H. Open Channel Block of Kv3.1 Currents by Fluoxetine. J. Pharmacol. Sci. 2008, 106, 38–45. [Google Scholar] [CrossRef] [Green Version]
- Brown, M.R.; El-Hassar, L.; Zhang, Y.; Alvaro, G.; Large, C.H.; Kaczmarek, L.K. Physiological Modulators of Kv3.1 Channels Adjust Firing Patterns of Auditory Brain Stem Neurons. J. Neurophysiol. 2016, 116, 106–121. [Google Scholar] [CrossRef] [Green Version]
- Quintero-Hernández, V.; Jiménez-Vargas, J.M.; Gurrola, G.B.; Valdivia, H.H.; Possani, L.D. Scorpion Venom Components That Affect Ion-Channels Function. Toxicon 2013, 76, 328–342. [Google Scholar] [CrossRef] [Green Version]
- Srairi-Abid, N.; Mansuelle, P.; Mejri, T.; Karoui, H.; Rochat, H.; Sampieri, F.; El Ayeb, M. Purification, Characterization and Molecular Modelling of Two Toxin-like Proteins from the Androctonus australis hector Venom: Natural Anatoxins. Eur. J. Biochem. 2000, 267, 5614–5620. [Google Scholar] [CrossRef]
- Khemili, D.; Valenzuela, C.; Laraba-Djebari, F.; Hammoudi-Triki, D. Differential effect of Androctonus australis hector venom components on macrophage KV channels: Electrophysiological characterization. Eur. Biophys. J. 2019, 48, 1–13. [Google Scholar] [CrossRef]
- Legros, C.; Céard, B.; Vacher, H.; Marchot, P.; Bougis, P.E.; Martin-Eauclaire, M.-F. Expression of the Standard Scorpion Alpha-Toxin AaH II and AaH II Mutants Leading to the Identification of Some Key Bioactive Elements. Biochim. Biophys. Acta (BBA) Gen. Subj. 2005, 1723, 91–99. [Google Scholar] [CrossRef]
- Bosmans, F.; Tytgat, J. Voltage-Gated Sodium Channel Modulation by Scorpion α-Toxins. Toxicon 2007, 49, 142–158. [Google Scholar] [CrossRef] [Green Version]
- Martin-Eauclaire, M.-F.; Ferracci, G.; Bosmans, F.; Bougis, P.E. A Surface Plasmon Resonance Approach to Monitor Toxin Interactions with an Isolated Voltage-Gated Sodium Channel Paddle Motif. J. Gen. Physiol. 2015, 145, 155–162. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- BenAissa, R.; Othman, H.; Villard, C.; Peigneur, S.; Mlayah-Bellalouna, S.; Abdelkafi-Koubaa, Z.; Marrakchi, N.; Essafi-Benkhadir, K.; Tytgat, J.; Luis, J.; et al. AaHIV a Sodium Channel Scorpion Toxin Inhibits the Proliferation of DU145 Prostate Cancer Cells. Biochem. Biophys. Res. Commun. 2020, 521, 340–346. [Google Scholar] [CrossRef] [PubMed]
- Clairfeuille, T.; Cloake, A.; Infield, D.T.; Llongueras, J.P.; Arthur, C.P.; Li, Z.R.; Jian, Y.; Martin-Eauclaire, M.-F.; Bougis, P.E.; Ciferri, C.; et al. Structural Basis of α-Scorpion Toxin Action on Nav Channels. Science 2019, 363, eaav8573. [Google Scholar] [CrossRef] [PubMed]
- Cheikh, A.; Benkhalifa, R.; Landoulsi, Z.; Chatti, I.; Ayeb, M.E. Inhibition of Human Kv3.1 Current Expressed in Xenopus Oocytes by the Toxic Venom Fraction of Androctonus australis hector. Arch. Pharm. Res. 2014, 37, 1445–1453. [Google Scholar] [CrossRef] [PubMed]
- Cid-Uribe, J.I.; Veytia-Bucheli, J.I.; Romero-Gutierrez, T.; Ortiz, E.; Possani, L.D. Scorpion Venomics: A 2019 Overview. Expert Rev. Proteom. 2020, 17, 67–83. [Google Scholar] [CrossRef]
- Rodríguez de la Vega, R.C.; Possani, L.D. Current Views on Scorpion Toxins Specific for K+-Channels. Toxicon 2004, 43, 865–875. [Google Scholar] [CrossRef]
- Hassani, O.; Loew, D.; Van Dorsselaer, A.; Papandréou, M.J.; Sorokine, O.; Rochat, H.; Sampieri, F.; Mansuelle, P. Aah VI, a Novel, N-Glycosylated Anti-Insect Toxin from Androctonus australis hector Scorpion Venom: Isolation, Characterisation, and Glycan Structure Determination. FEBS Lett. 1999, 443, 175–180. [Google Scholar] [CrossRef] [Green Version]
- Loret, E.P.; Mansuelle, P.; Rochat, H.; Granier, C. Neurotoxins Active on Insects: Amino Acid Sequences, Chemical Modifications, and Secondary Structure Estimation by Circular Dichroism of Toxins from the Scorpion Androctonus australis hector. Biochemistry 1990, 29, 1492–1501. [Google Scholar] [CrossRef] [PubMed]
- Darbon, H. Two-Dimensional Proton Nuclear Magnetic Resonance Study of AaH IT, an Anti-Insect Toxin from the Scorpion Androctonus australis hector. Sequential Resonance Assignments and Folding of the Polypeptide Chain. Biochemistry 1991, 30, 1836–1845. [Google Scholar] [CrossRef]
- Jourdon, P.; Berwald-Netter, Y.; Houzet, E.; Couraud, F.; Dubois, J.M. Effects of Toxin II from the Scorpion Androctonus australis hector on Sodium Current in Neuroblastoma Cells and Their Modulation by Oleic Acid. Eur. Biophys. J. 1989, 16, 351–356. [Google Scholar] [CrossRef]
- Duval, A.; Malécot, C.O.; Pelhate, M.; Rochat, H. Changes in Na Channel Properties of Frog and Rat Skeletal Muscles Induced by the AaH II Toxin from the Scorpion Androctonus australis. Pflügers Arch. 1989, 415, 361–371. [Google Scholar] [CrossRef]
- Alami, M.; Vacher, H.; Bosmans, F.; Devaux, C.; Rosso, J.-P.; Bougis, P.E.; Tytgat, J.; Darbon, H.; Martin-Eauclaire, M.-F. Characterization of Amm VIII from Androctonus Mauretanicus Mauretanicus: A New Scorpion Toxin That Discriminates between Neuronal and Skeletal Sodium Channels. Biochem. J. 2003, 375, 551–560. [Google Scholar] [CrossRef]
- Abbas, N.; Gaudioso-Tyzra, C.; Bonnet, C.; Gabriac, M.; Amsalem, M.; Lonigro, A.; Padilla, F.; Crest, M.; Martin-Eauclaire, M.-F.; Delmas, P. The Scorpion Toxin Amm VIII Induces Pain Hypersensitivity through Gain-of-Function of TTX-Sensitive Na+ Channels. Pain 2013, 154, 1204–1215. [Google Scholar] [CrossRef]
- Mikou, A.; LaPlante, S.R.; Guittet, E.; Lallemand, J.Y.; Martin-Eau Claire, M.F.; Rochat, H. Toxin III of the Scorpion Androctonus australis hector: Proton Nuclear Magnetic Resonance Assignments and Secondary Structure. J. Biomol. NMR 1992, 2, 57–70. [Google Scholar] [CrossRef] [PubMed]
- Kharrat, R.; Darbon, H.; Rochat, H.; Granier, C. Structure/Activity Relationships of Scorpion Alpha-Toxins. Multiple Residues Contribute to the Interaction with Receptors. Eur. J. Biochem. 1989, 181, 381–390. [Google Scholar] [CrossRef]
- Blanc, E.; Hassani, O.; Meunier, S.; Mansuelle, P.; Sampieri, F.; Rochat, H.; Darbon, H. 1H-NMR-Derived Secondary Structure and Overall Fold of a Natural Anatoxin from the Scorpion Androctonus australis hector. Eur. J. Biochem. 1997, 247, 1118–1126. [Google Scholar] [CrossRef] [PubMed]
- Legros, C.; Céard, B.; Bougis, P.E.; Martin-Eauclaire, M.-F. Evidence for a New Class of Scorpion Toxins Active against K+ Channels. FEBS Lett. 1998, 431, 375–380. [Google Scholar] [CrossRef] [Green Version]
- Landoulsi, Z.; Miceli, F.; Palmese, A.; Amoresano, A.; Marino, G.; El Ayeb, M.; Taglialatela, M.; Benkhalifa, R. Subtype-Selective Activation of Kv7 Channels by AaTXK β (2–64), a Novel Toxin Variant from the Androctonus Australis Scorpion Venom. Mol. Pharmacol. 2013, 84, 763–773. [Google Scholar] [CrossRef] [Green Version]
- Pisciotta, M.; Ottolia, M.; Possani, L.D.; Prestipino, G. A Novel Toxin from the Scorpion Androctonus australis Blocks Shaker K+ Channels Expressed in Xenopus Oocytes. Biochem. Biophys. Res. Commun. 1998, 242, 287–291. [Google Scholar] [CrossRef]
- Mlayah-Bellalouna, S.; Dufour, M.; Mabrouk, K.; Mejdoub, H.; Carlier, E.; Othman, H.; Belghazi, M.; Tarbe, M.; Goaillard, J.M.; Gigmes, D.; et al. AaTX1, from Androctonus australis scorpion venom: Purification, synthesis and characterization in dopaminergic neurons. Toxicon 2014, 92, 14–23. [Google Scholar] [CrossRef] [PubMed]
- Vacher, H.; Romi-Lebrun, R.; Crest, M.; Masmejean, F.; Bougis, P.E.; Darbon, H.; Martin-Eauclaire, M.-F. Functional Consequences of Deleting the Two C-Terminal Residues of the Scorpion Toxin BmTX3. Biochim. Biophys. Acta (BBA) Proteins Proteom. 2003, 1646, 152–156. [Google Scholar] [CrossRef]
- Abdel-Mottaleb, Y.; Corzo, G.; Martin-Eauclaire, M.-F.; Satake, H.; Céard, B.; Peigneur, S.; Nambaru, P.; Bougis, P.-E.; Possani, L.D.; Tytgat, J. A Common “Hot Spot” Confers HERG Blockade Activity to α-Scorpion Toxins Affecting K+ Channels. Biochem. Pharmacol. 2008, 76, 805–815. [Google Scholar] [CrossRef] [PubMed]
- Lee, H.M.; Chai, O.H.; Hahn, S.J.; Choi, B.H. Antidepressant Drug Paroxetine Blocks the Open Pore of Kv3.1 Potassium Channel. Korean J. Physiol. Pharmacol. 2018, 22, 71. [Google Scholar] [CrossRef] [Green Version]
- Sung, M.J.; Hahn, S.J.; Choi, B.H. Effect of Psoralen on the Cloned Kv3.1 Currents. Arch. Pharm. Res. 2009, 32, 407–412. [Google Scholar] [CrossRef] [PubMed]
- Diochot, S.; Schweitz, H.; Béress, L.; Lazdunski, M. Sea Anemone Peptides with a Specific Blocking Activity against the Fast Inactivating Potassium Channel Kv3.4. J. Biol. Chem. 1998, 273, 6744–6749. [Google Scholar] [CrossRef] [Green Version]
- Yeung, S.Y.M. Modulation of Kv3 Subfamily Potassium Currents by the Sea Anemone Toxin BDS: Significance for CNS and Biophysical Studies. J. Neurosci. 2005, 25, 8735–8745. [Google Scholar] [CrossRef] [Green Version]
- Kopljar, I.; Labro, A.J.; de Block, T.; Rainier, J.D.; Tytgat, J.; Snyders, D.J. The Ladder-Shaped Polyether Toxin Gambierol Anchors the Gating Machinery of Kv3.1 Channels in the Resting State. J. Gen. Physiol. 2013, 141, 359–369. [Google Scholar] [CrossRef] [Green Version]
- Pisciotta, M.; Coronas, F.I.; Bloch, C.; Prestipino, G.; Possani, L.D. Fast K+ Currents from Cerebellum Granular Cells Are Completely Blocked by a Peptide Puri¢ed from Androctonus australis Garzoni Scorpion Venom. Biochim. Biophys. Acta (BBA) Biomembr. 2000, 1468, 203–212. [Google Scholar] [CrossRef] [Green Version]
- Vacher, H.; Romi-Lebrun, R.; Mourre, C.; Lebrun, B.; Kourrich, S.; Masméjean, F.; Nakajima, T.; Legros, C.; Crest, M.; Bougis, P.E.; et al. A New Class of Scorpion Toxin Binding Sites Related to an A-Type K+ Channel: Pharmacological Characterization and Localization in Rat Brain. FEBS Lett. 2001, 501, 31–36. [Google Scholar] [CrossRef] [Green Version]
- Vacher, H.; Alami, M.; Crest, M.; Possani, L.D.; Bougis, P.E.; Martin-Eauclaire, M.-F. Expanding the Scorpion Toxin α-KTX 15 Family with AmmTX3 from Androctonus Mauretanicus: Expanding the Scorpion Toxin α-KTX 15 Family. Eur. J. Biochem. 2002, 269, 6037–6041. [Google Scholar] [CrossRef]
- Vacher, H.; Diochot, S.; Bougis, P.E.; Martin-Eauclaire, M.-F.; Mourre, C. Kv4 Channels Sensitive to BmTX3 in Rat Nervous System: Autoradiographic Analysis of Their Distribution during Brain Ontogenesis. Eur. J. Neurosci. 2006, 24, 1325–1340. [Google Scholar] [CrossRef] [PubMed]
- Maffie, J.K.; Dvoretskova, E.; Bougis, P.E.; Martin-Eauclaire, M.-F.; Rudy, B. Dipeptidyl-Peptidase-like-Proteins Confer High Sensitivity to the Scorpion Toxin AmmTX3 to Kv4-Mediated A-Type K+ Channels: DPP Proteins Confer Toxin Sensitivity to Kv4 Channels. J. Physiol. 2013, 591, 2419–2427. [Google Scholar] [CrossRef] [PubMed]
- Aidi-knani, S.; Regaya, I.; Amalric, M.; Mourre, C. Kv4 Channel Blockade Reduces Motor and Neuropsychiatric Symptoms in Rodent Models of Parkinson’s Disease. Behav. Pharmacol. 2015, 26, 91–100. [Google Scholar] [CrossRef] [Green Version]
- MacKinnon, R.; Miller, C. Mutant Potassium Channels with Altered Binding of Charybdotoxin, a Pore-Blocking Peptide Inhibitor. Science 1989, 245, 1382–1385. [Google Scholar] [CrossRef]
- Giangiacomo, K.M.; Garcia, M.L.; McManus, O.B. Mechanism of Iberiotoxin Block of the Large-Conductance Calcium-Activated Potassium Channel from Bovine Aortic Smooth Muscle. Biochemistry 1992, 31, 6719–6727. [Google Scholar] [CrossRef]
- Aiyar, J.; Rizzi, J.P.; Gutman, G.A.; Chandy, K.G. The Signature Sequence of Voltage-Gated Potassium Channels Projects into the External Vestibule. J. Biol. Chem. 1996, 271, 31013–31016. [Google Scholar] [CrossRef] [Green Version]
- Vita, C.; Bontems, F.; Bouet, F.; Tauc, M.; Poujeol, P.; Vatanpour, H.; Harvey, A.L.; Menez, A.; Toma, F. Synthesis of Charybdotoxin and of Two N-Terminal Truncated Analogues. Structural and Functional Characterisation. Eur. J. Biochem. 1993, 217, 157–169. [Google Scholar] [CrossRef]
- Srairi-Abid, N.; Guijarro, J.I.; Benkhalifa, R.; Mantegazza, M.; Cheikh, A.; Ben Aissa, M.; Haumont, P.-Y.; Delepierre, M.; El Ayeb, M. A New Type of Scorpion Na+-Channel-Toxin-like Polypeptide Active on K+ Channels. Biochem. J. 2005, 388, 455–464. [Google Scholar] [CrossRef]
- Jukkola, P.; Gu, Y.; Lovett-Racke, A.E.; Gu, C. Suppression of Inflammatory Demyelinaton and Axon Degeneration through Inhibiting Kv3 Channels. Front. Mol. Neurosci. 2017, 10, 344. [Google Scholar] [CrossRef] [Green Version]
- Song, M.; Park, S.; Park, J.; Byun, J.; Jin, H.; Seo, S.; Ryu, P.; Lee, S. Kv3.1 and Kv3.4, Are Involved in Cancer Cell Migration and Invasion. Int. J. Mol. Sci. 2018, 19, 1061. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Serôdio, P.; Rudy, B. Differential Expression of Kv4 K+ Channel Subunits Mediating Subthreshold Transient K+ (A-Type) Currents in Rat Brain. J. Neurophysiol. 1998, 79, 1081–1091. [Google Scholar] [CrossRef] [Green Version]
- Serodio, P.; Vega-Saenz de Miera, E.; Rudy, B. Cloning of a Novel Component of A-Type K+ Channels Operating at Subthreshold Potentials with Unique Expression in Heart and Brain. J. Neurophysiol. 1996, 75, 2174–2179. [Google Scholar] [CrossRef]
- Wickenden, A.D. K+ Channels as Therapeutic Drug Targets. Pharmacol. Ther. 2002, 94, 157–182. [Google Scholar] [CrossRef]
- Rice, P. EMBOSS: The European Molecular Biology Open Software Suite. Trends Genet. 2000, 16, 276–277. [Google Scholar] [CrossRef]
- Sali, A.; Blundell, T.L. Comparative Protein Modelling by Satisfaction of Spatial Restraints. J. Mol. Biol. 1993, 234, 779–815. [Google Scholar] [CrossRef]
- Zoukimian, C.; Meudal, H.; De Waard, S.; Ouares, K.A.; Nicolas, S.; Canepari, M.; Béroud, R.; Landon, C.; De Waard, M.; Boturyn, D. Synthesis by Native Chemical Ligation and Characterization of the Scorpion Toxin AmmTx3. Bioorg. Med. Chem. 2019, 27, 247–253. [Google Scholar] [CrossRef]
- Shen, M.; Sali, A. Statistical Potential for Assessment and Prediction of Protein Structures. Protein Sci. 2006, 15, 2507–2524. [Google Scholar] [CrossRef] [Green Version]
- Ramachandran, G.N.; Ramakrishnan, C.; Sasisekharan, V. Stereochemistry of Polypeptide Chain Configurations. J. Mol. Biol. 1963, 7, 95–99. [Google Scholar] [CrossRef]
- Sippl, M.J. Recognition of Errors in Three-Dimensional Structures of Proteins. Proteins 1993, 17, 355–362. [Google Scholar] [CrossRef] [PubMed]
- Luthy, R.; Bowie, J.U.; Eisemberg, D. Assessment of protein models with three-dimensional profiles. Nature 1992, 356, 83–85. [Google Scholar] [CrossRef] [PubMed]
- Martin-Eauclaire, M.-F.; Bougis, P.E. Potassium Channels Blockers from the Venom of Androctonus Mauretanicus Mauretanicus. J. Toxicol. 2012, 2012, 103608. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kozakov, D.; Hall, D.R.; Xia, B.; Porter, K.A.; Padhorny, D.; Yueh, C.; Beglov, D.; Vajda, S. The ClusPro Web Server for Protein–Protein Docking. Nat. Protoc. 2017, 12, 255–278. [Google Scholar] [CrossRef] [PubMed]
Control | AahG50 | F5 | H7 | |
---|---|---|---|---|
Midpoint potential (V1/2) (mV) | 0.28 ± 0.06 | 11.32 ± 0.07 | 16.70 ± 0.26 | 12.22 ± 0.24 |
Slope factor (k) (mV) | 10.91 ± 0.05 | 15.71 ± 0.07 | 13.44 ± 0.24 | 12.69 ± 0.19 |
Threshold potential (Thresh) (mV) | −20 | −20 | −20 | −20 |
Toxins | Ion Channel Activity |
---|---|
Aah6 | Anti-insect beta-toxins: bind in a voltage-independent manner at site-4 of Na+ channels and shift the voltage of activation toward more negative potentials [27]. |
Beta-insect excitatory 1 OS | Beta toxins: specifically active on the insect nervous system by affecting Na+ channel activation and promoting spontaneous and repetitive firing [28,29]. |
Aah2 | Alpha toxins: bind in a voltage-independent manner at site-3 of Na+ channels (Nav) and block neuronal transmission. The toxin principally slows the inactivation process of TTX-sensitive Na+ channels [19,30,31,32,33]. AaH2 sterically occludes VSD4 activation by forming a number of interactions that serve to pin the S3-S4 loop and S4 helix into a deactivated conformation [23]. |
Aah3 | Alpha toxins: binds in a voltage-independent manner at site-3 of Na+ channels (Nav) and inhibit the inactivation of the activated channels, thereby blocking neuronal transmission [34,35]. |
Neurotoxin-like protein STR 1 (50% similarity with Aah6) | Non-toxic polypeptide: active on Na+ channel [36]. |
G-TI | Kunitz trypsin inhibitor inhibits Na+ channel. |
AaTXK-beta | Beta-KTx: peptide activator of Kv7.4, Kv7.3 and Kv7.2/Kv7.3 channels. [37,38]. |
Alpha-KTx 15.1 | Alpha-KTx: inhibits transient K+ channels (IA-type current) by occluding the outer entry to the K+ conducting pore [39,40,41,42]. |
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Maatoug, S.; Cheikh, A.; Khamessi, O.; Tabka, H.; Landoulsi, Z.; Guigonis, J.-M.; Diochot, S.; Bendahhou, S.; Benkhalifa, R. Cross Pharmacological, Biochemical and Computational Studies of a Human Kv3.1b Inhibitor from Androctonus australis Venom. Int. J. Mol. Sci. 2021, 22, 12290. https://doi.org/10.3390/ijms222212290
Maatoug S, Cheikh A, Khamessi O, Tabka H, Landoulsi Z, Guigonis J-M, Diochot S, Bendahhou S, Benkhalifa R. Cross Pharmacological, Biochemical and Computational Studies of a Human Kv3.1b Inhibitor from Androctonus australis Venom. International Journal of Molecular Sciences. 2021; 22(22):12290. https://doi.org/10.3390/ijms222212290
Chicago/Turabian StyleMaatoug, Sonia, Amani Cheikh, Oussema Khamessi, Hager Tabka, Zied Landoulsi, Jean-Marie Guigonis, Sylvie Diochot, Saïd Bendahhou, and Rym Benkhalifa. 2021. "Cross Pharmacological, Biochemical and Computational Studies of a Human Kv3.1b Inhibitor from Androctonus australis Venom" International Journal of Molecular Sciences 22, no. 22: 12290. https://doi.org/10.3390/ijms222212290