| Structural highlights
Function
[TOG4A_AGEAP] Omega-agatoxins inhibit neuronal voltage-gated calcium channels. This toxin acts by modifying the gating of the high voltage activated P-type Cav2.1/CACNA1A channel. Is a potent blocker in both insect and mammalian central neurons.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
To analyze structural features of omega-Aga IVA, a gating modifier toxin from spider venom, we here investigated the NMR solution structure of omega-Aga IVA within DPC micelles. Under those conditions, the Cys-rich central region of omega-Aga IVA still retains the inhibitor Cys knot motif with three short antiparallel beta-strands seen in water. However, 15N HSQC spectra of omega-Aga IVA within micelles revealed that there are radical changes to the toxin's C-terminal tail and several loops upon binding to micelles. The C-terminal tail of omega-Aga IVA appears to assume a beta-turn like conformation within micelles, though it is disordered in water. Whole-cell patch clamp studies with several omega-Aga IVA analogs indicate that both the hydrophobic C-terminal tail and an Arg patch in the core region of omega-Aga IVA are critical for Cav2.1 blockade. These results suggest that the membrane environment stabilizes the structure of the toxin, enabling it to act in a manner similar to other gating modifier toxins, though its mode of interaction with the membrane and the channel is unique.
Structure-activity relationships of omega-Agatoxin IVA in lipid membranes.,Ryu JH, Jung HJ, Konishi S, Kim HH, Park ZY, Kim JI Biochem Biophys Res Commun. 2017 Jan 1;482(1):170-175. doi:, 10.1016/j.bbrc.2016.11.025. Epub 2016 Nov 9. PMID:27838299[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mintz IM, Venema VJ, Swiderek KM, Lee TD, Bean BP, Adams ME. P-type calcium channels blocked by the spider toxin omega-Aga-IVA. Nature. 1992 Feb 27;355(6363):827-9. PMID:1311418 doi:https://dx.doi.org/10.1038/355827a0
- ↑ Nishio H, Kumagaye KY, Kubo S, Chen YN, Momiyama A, Takahashi T, Kimura T, Sakakibara S. Synthesis of omega-agatoxin IVA and its related peptides. Biochem Biophys Res Commun. 1993 Nov 15;196(3):1447-53. PMID:8250902 doi:https://dx.doi.org/10.1006/bbrc.1993.2414
- ↑ Bickmeyer U, Rossler W, Wiegand H. Omega AGA toxin IVA blocks high-voltage-activated calcium channel currents in cultured pars intercerebralis neurosecretory cells of adult locusta migratoria. Neurosci Lett. 1994 Nov 7;181(1-2):113-6. PMID:7898748
- ↑ McDonough SI, Mintz IM, Bean BP. Alteration of P-type calcium channel gating by the spider toxin omega-Aga-IVA. Biophys J. 1997 May;72(5):2117-28. PMID:9129813 doi:https://dx.doi.org/10.1016/S0006-3495(97)78854-4
- ↑ Wicher D, Penzlin H. Ca2+ currents in central insect neurons: electrophysiological and pharmacological properties. J Neurophysiol. 1997 Jan;77(1):186-99. PMID:9120560
- ↑ Winterfield JR, Swartz KJ. A hot spot for the interaction of gating modifier toxins with voltage-dependent ion channels. J Gen Physiol. 2000 Nov;116(5):637-44. PMID:11055992
- ↑ Wang XH, Connor M, Wilson D, Wilson HI, Nicholson GM, Smith R, Shaw D, Mackay JP, Alewood PF, Christie MJ, King GF. Discovery and structure of a potent and highly specific blocker of insect calcium channels. J Biol Chem. 2001 Oct 26;276(43):40306-12. Epub 2001 Aug 24. PMID:11522785 doi:https://dx.doi.org/10.1074/jbc.M105206200
- ↑ Ryu JH, Jung HJ, Konishi S, Kim HH, Park ZY, Kim JI. Structure-activity relationships of omega-Agatoxin IVA in lipid membranes. Biochem Biophys Res Commun. 2017 Jan 1;482(1):170-175. doi:, 10.1016/j.bbrc.2016.11.025. Epub 2016 Nov 9. PMID:27838299 doi:https://dx.doi.org/10.1016/j.bbrc.2016.11.025
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