6mk4 | pdb_00006mk4
Solution NMR structure of spider toxin analogue [E17K]ProTx-II
Structural highlights
FunctionTXPR2_THRPR Blocks both tetrodotoxin-sensitive and tetrodotoxin-resistant human voltage-gated sodium channels by shifting the voltage dependence of channel activation to more positive potentials. Inhibits Nav1.2/SCN2A, Nav1.3/SCN3A, Nav1.5/SCN5A, Nav1.6/SCN8A, Nav1.7/SCN9A, Nav1.8/SCN10A. Is significantly more potent against Nav1.7/SCN9A than the other Nav channel subtypes. Has no significant effect on Kv1.2/KCNA2, Kv1.3/KCNA3, Kv1.5/KCNA5, and Kv2.1/KCNB1 channels. Also inhibits Cav1.2/CACNA1C and Cav3.1/CACNA1G channels with an IC(50) around 100 nM. Does not bind to the pharmacologically defined Nav channel sites 3 or 4. Neutralization of gating charges in the voltage sensor (S4) of domain II of Nav1.2/SCN2A prevents the effect of the toxin on gating current. Thus, it has been suggested that the toxin acts by trapping the voltage sensor of Nav channel domain II in the resting state, impeding outward gating movement of the IIS4 transmembrane segment of the channel. Binds to phospholipids.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedGating modifier toxins (GMTs) from spider venom can inhibit voltage gated sodium channels (NaVs) involved in pain signal transmission, including the NaV1.7 subtype. GMTs have a conserved amphipathic structure that allow them to interact with membranes and also with charged residues in regions of NaV that are exposed at the cell surface. ProTx-II and GpTx-1 are GMTs able to inhibit NaV1.7 with high potency, but they differ in their ability to bind to membranes and in their selectivity over other NaV subtypes. To explore these differences and gain detailed information on their membrane-binding ability and how this relates to potency and selectivity, we examined previously described NaV1.7 potent/selective GpTx-1 analogues, and new ProTx-II analogues designed to reduce membrane binding and improve selectivity for NaV1.7. Our studies reveal that the number and type of hydrophobic residues as well as how they are presented at the surface determine the affinity of ProTx-II and GpTx-1 for membranes, and that altering these residues can have dramatic effects on NaV inhibitory activity. We demonstrate that strong peptide-membrane interactions are not essential for inhibiting NaV1.7, and propose that hydrophobic interactions instead play an important role in positioning the GMT at the membrane surface proximal to exposed NaV residues, thereby affecting peptide-channel interactions. Our detailed structure activity relationship study highlights the challenges of designing GMT-based molecules that simultaneously achieve high potency and selectivity for NaV1.7, as single mutations can induce local changes in GMT structure that can have a major impact on NaV-inhibitory activity. Peptide-membrane interactions affect the inhibitory potency and selectivity of spider toxins ProTx-II and GpTx-1.,Lawrence N, Wu B, Ligutti J, Cheneval O, Agwa AJ, Benfield AH, Biswas K, Craik DJ, Miranda LP, Troeira Henriques S, Schroeder CI ACS Chem Biol. 2018 Dec 3. doi: 10.1021/acschembio.8b00989. PMID:30507158[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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