Gating-modifier toxin that targets voltage-gated sodium channels with a selective activity on Nav1.7/SCN9A (IC(50)=1-1.5 nM) (PubMed:25026046, PubMed:31234412). It inhibits both activation and inactivation (PubMed:20855463). For inhibition of activation, it is 100-fold more selective for Nav1.7/SCN9A (IC(50)=0.26-3) than for other sodium channels (Nav1.2/SCN2A (IC(50)=40-540 nM), Nav1.3/SCN3A (IC(50)=102 nM), Nav1.4/SCN4A (IC(50)=30-39 nM), Nav1.5/SCN5A (IC(50)=19-90 nM), Nav1.6/SCN8A (IC(50)=26 nM), and Nav1.8/SCN10A (IC(50)=146 nM)) (PubMed:12475222, PubMed:17087985, PubMed:18156314, PubMed:18728100, PubMed:20855463, PubMed:25658507, PubMed:27311819, PubMed:30661758). For inhibition of inactivation, it is 20-fold more potent in inhibiting inactivation on Nav1.7/SCN9A (IC(50)=250 nM) than other channels (about 4.6 uM for all channels) (PubMed:20855463). It also weakly inhibits Cav1.2/CACNA1C and Cav3.2/CACNA1H (29% block at 1 uM) (PubMed:17087985, PubMed:20600227, PubMed:24886690). It inhibits Nav1.7/SCN9A activation by interacting with DII and impairs Nav1.7/SCN9A inactivation by interacting with DIV (PubMed:20855463). It docks on top of the DII S3 helix Nav1.7/SCN9A (PubMed:30661758, PubMed:30765606). It is about 60-fold less active on Nav1.7/SCN9A at depolarized potential (0 mV; IC(50)=15 nM), compared to -120 mV potential (IC(50)=0.26 nM) (PubMed:30661758). This toxin binds to lipid membrane (PubMed:15632158, PubMed:27311819). This ability correlates with hNav1.7/SCN9A inhibition, showing that membrane binding is the first step in the inhibitory mechanism of this toxin (PubMed:27311819). It inhibits Nav1.2/SCN2A less potently when it is coexpressed with SCN2B or SCN4B than when it is expressed alone, showing that beta subunits (SCN2B and SCN4B) have a protective effect (PubMed:24297919, PubMed:26894959). Expressed by the venom gland. The presence of a 'disulfide through disulfide knot' structurally defines this protein as a knottin. The derivative JNJ63955918 (Y1GPY; W7Q; W30L) is under preclinical trial by Janssen Pharmaceutica as a non-opioid alternative for the pharmacological treatment of severe pain. The ability to inhibit Nav1.7/SCN9A is greatly enhances by unatural modifications such as C-terminal amidation (5-fold) or C-terminal addition of -NHCH3 (25-fold). Such modifications also improve the ability to inhibit Nav1.2/SCN2A, but the selectivity for Nav1.7/SCN9A over Nav1.2/SCN2A is retained. Highly resistant to proteases, such as pepsin, trypsin, chymotrypsin and elastase. The toxin is not degraded in the plasma and shows fast clearance from the circulation. Does not inhibit Kv1.2/KCNA2, Kv1.3/KCNA3, Kv1.5/KCNA5, and Kv2.1/KCNB1 channels (PubMed:12475222). Weakly inhibits calcium channels hCav3.1/CACNA1G (9% inhibition at 1 uM or 81% at 5 uM) and hCav3.3/CACNA1I (8.9% inhibition at 1 uM) (PubMed:24886690). Belongs to the neurotoxin 30 (phrixotoxin) family.