8cjq | pdb_00008cjq
JzTx-34 toxin peptide E20A mutant
Structural highlights
FunctionJZT34_CHIGU Potent and selective inhibitor of hNav1.7/SCN9A (IC(50)=610 nM) (PubMed:29393892). Also shows a weak activity towards Nav1.3/SCN3A (IC(50)=7950 nM) (PubMed:29393892). In addition, inhibits voltage-gated potassium channels (Kv) in rat DRG neurons (PubMed:18581053). It does not alter the voltage dependence of activation, but it causes a small hyperpolarizing shift in the steady-state inactivations of Nav1.7/SNC9A (PubMed:29393892). Chimera experiments show that the toxin binds to the DIIS3-S4 linker (site 4) of Nav1.7/SCN9A, whereas Nav1.7/SCN9A Asp-827 residue is shown by substitution experiments to be critical for its sensitivity (PubMed:19463735, PubMed:29393892). The toxin traps the domain II voltage sensor in the closed configuration, and not in an outward position (PubMed:29393892). In vivo, shows analgesic activity in three rodent pain models (formalin-induced, acid-induced, and thermal) (PubMed:29393892).[1] [2] [3] Publication Abstract from PubMedNa(v)1.1 is an important pharmacological target as this voltage-gated sodium channel is involved in neurological and cardiac syndromes. Channel activators are actively sought to try to compensate for haploinsufficiency in several of these pathologies. Herein we used a natural source of new peptide compounds active on ion channels and screened for drugs capable to inhibit channel inactivation as a way to compensate for decreased channel function. We discovered that JzTx-34 is highly active on Na(v)1.1 and subsequently performed a full structure-activity relationship investigation to identify its pharmacophore. These experiments will help interpret the mechanism of action of this and formerly identified peptides as well as the future identification of new peptides. We also reveal structural determinants that make natural ICK peptides active against Na(v)1.1 challenging to synthesize. Altogether, the knowledge gained by this study will help facilitate the discovery and development of new compounds active on this critical ion channel target. Structure-function relationship of new peptides activating human Na(v)1.1.,Lopez L, De Waard S, Meudal H, Caumes C, Khakh K, Peigneur S, Oliveira-Mendes B, Lin S, De Waele J, Montnach J, Cestele S, Tessier A, Johnson JP, Mantegazza M, Tytgat J, Cohen C, Beroud R, Bosmans F, Landon C, De Waard M Biomed Pharmacother. 2023 Jul 13;165:115173. doi: 10.1016/j.biopha.2023.115173. PMID:37453200[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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