8cjq

From Proteopedia

JzTx-34 toxin peptide E20A mutant

Structural highlights

8cjq is a 1 chain structure with sequence from Chilobrachys. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

JZT34_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 PubMed

Na(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

↑ Chen J, Deng M, He Q, Meng E, Jiang L, Liao Z, Rong M, Liang S. Molecular diversity and evolution of cystine knot toxins of the tarantula Chilobrachys jingzhao. Cell Mol Life Sci. 2008 Aug;65(15):2431-44. PMID:18581053 doi:http://dx.doi.org/10.1007/s00018-008-8135-x
↑ Zeng X, Li P, Chen B, Huang J, Lai R, Liu J, Rong M. Selective Closed-State Nav1.7 Blocker JZTX-34 Exhibits Analgesic Effects against Pain. Toxins (Basel). 2018 Feb 2;10(2):64. PMID:29393892 doi:10.3390/toxins10020064
↑ Chen J, Zhang Y, Rong M, Zhao L, Jiang L, Zhang D, Wang M, Xiao Y, Liang S. Expression and characterization of jingzhaotoxin-34, a novel neurotoxin from the venom of the tarantula Chilobrachys jingzhao. Peptides. 2009 Jun;30(6):1042-8. PMID:19463735 doi:10.1016/j.peptides.2009.02.018
↑ Lopez L, De Waard S, Meudal H, Caumes C, Khakh K, Peigneur S, Oliveira-Mendes B, Lin S, De Waele J, Montnach J, Cestèle S, Tessier A, Johnson JP, Mantegazza M, Tytgat J, Cohen C, Béroud R, Bosmans F, Landon C, De Waard M. Structure-function relationship of new peptides activating human Na(v)1.1. Biomed Pharmacother. 2023 Jul 13;165:115173. PMID:37453200 doi:10.1016/j.biopha.2023.115173