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5tlr
From Proteopedia
Solution NMR structure of gHwTx-IV
Structural highlights
FunctionTXH4_CYRSC This lethal neurotoxin (without cyclization at position 53) inhibits neuronal voltage-gated sodium channel Nav1.2/SCN2A (IC(50)=10-150 nM), rNav1.3/SCN3A (IC(50)=338 nM), Nav1.6/SCN8A (IC(50)=117 nM), and hNav1.7/SCN9A (IC(50)=9.6-33 nM) (PubMed:18628201, PubMed:20855463, PubMed:25658507, PubMed:29703751,PubMed:31234412, PubMed:23760503). It inhibits activation of sodium channel by trapping the voltage sensor of domain II (DIIS4) in the closed configuration (PubMed:18628201, PubMed:23760503). The toxin neither shifts the Nav1.7/SCN9A activation curve nor modifies the slope factor (PubMed:20855463). It does not slow fast-inactivation of hNav1.7/SCN9A channels (PubMed:20855463). In addition, it has only a weak affinity for lipid membranes (PubMed:18054060, PubMed:29703751, PubMed:28115115). This toxin also exists with a pyroglutamate at position 53 (PubMed:23826086). The sole difference observed between modified (mHwTx-IV) and unmodified toxins is that moderate or high depolarization voltages (200 mV) permit the unmodified toxin to dissociate, whereas mHwTx-IV toxin does not dissociate, even at high depolarization voltages (PubMed:23826086). These data indicate that mHwTx-IV strongly binds to voltage sensor of sodium channel even at extreme depolarization voltages (PubMed:23826086).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Publication Abstract from PubMedThe human voltage-gated sodium channel sub-type 1.7 (hNaV1.7) is emerging as an attractive target for the development of potent and sub-type selective novel analgesics with increased potency and fewer side effects than existing therapeutics. HwTx-IV, a spider derived peptide toxin, inhibits hNaV1.7 with high potency and is therefore of great interest as an analgesic lead. In the current study we examined whether engineering a HwTx-IV analogue with increased ability to bind to lipid membranes would improve its inhibitory potency at hNaV1.7. This hypothesis was explored by comparing HwTx-IV and two analogues [E1PyrE]HwTx-IV (mHwTx-IV) and [E1G,E4G,F6W,Y30W]HwTx-IV (gHwTx-IV) on their membrane-binding affinity and hNaV1.7 inhibitory potency using a range of biophysical techniques including computational analysis, NMR spectroscopy, surface plasmon resonance, and fluorescence spectroscopy. HwTx-IV and mHwTx-IV exhibited weak affinity for lipid membranes, whereas gHwTx-IV showed improved affinity for the model membranes studied. In addition, activity assays using SH-SY5Y neuroblastoma cells expressing hNaV1.7 showed that gHwTx-IV has increased activity at hNaV1.7 compared to HwTx-IV. Based on these results we hypothesize that an increase in the affinity of HwTx-IV for lipid membranes is accompanied by improved inhibitory potency at hNaV1.7 and that increasing the affinity of gating modifier toxins to lipid bilayers is a strategy that may be useful for improving their potency at hNaV1.7. Spider peptide toxin HwTx-IV engineered to bind to lipid membranes has an increased inhibitory potency at human voltage-gated sodium channel hNaV1.7.,Agwa AJ, Lawrence N, Deplazes E, Cheneval O, Chen RM, Craik DJ, Schroeder CI, Henriques ST Biochim Biophys Acta. 2017 Jan 20;1859(5):835-844. doi:, 10.1016/j.bbamem.2017.01.020. PMID:28115115[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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