6mk4

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(Difference between revisions)

Revision as of 10:54, 14 June 2023

Solution NMR structure of spider toxin analogue [E17K]ProTx-II

Structural highlights

6mk4 is a 1 chain structure with sequence from Thrixopelma pruriens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TXPR2_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 PubMed

Gating 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

↑ Middleton RE, Warren VA, Kraus RL, Hwang JC, Liu CJ, Dai G, Brochu RM, Kohler MG, Gao YD, Garsky VM, Bogusky MJ, Mehl JT, Cohen CJ, Smith MM. Two tarantula peptides inhibit activation of multiple sodium channels. Biochemistry. 2002 Dec 17;41(50):14734-47. PMID:12475222
↑ Priest BT, Blumenthal KM, Smith JJ, Warren VA, Smith MM. ProTx-I and ProTx-II: gating modifiers of voltage-gated sodium channels. Toxicon. 2007 Feb;49(2):194-201. Epub 2006 Sep 27. PMID:17087985 doi:http://dx.doi.org/10.1016/j.toxicon.2006.09.014
↑ Smith JJ, Cummins TR, Alphy S, Blumenthal KM. Molecular interactions of the gating modifier toxin ProTx-II with NaV 1.5: implied existence of a novel toxin binding site coupled to activation. J Biol Chem. 2007 Apr 27;282(17):12687-97. Epub 2007 Mar 5. PMID:17339321 doi:http://dx.doi.org/10.1074/jbc.M610462200
↑ Sokolov S, Kraus RL, Scheuer T, Catterall WA. Inhibition of sodium channel gating by trapping the domain II voltage sensor with protoxin II. Mol Pharmacol. 2008 Mar;73(3):1020-8. Epub 2007 Dec 21. PMID:18156314 doi:http://dx.doi.org/10.1124/mol.107.041046
↑ Edgerton GB, Blumenthal KM, Hanck DA. Evidence for multiple effects of ProTxII on activation gating in Na(V)1.5. Toxicon. 2008 Sep 1;52(3):489-500. Epub 2008 Jul 9. PMID:18657562 doi:http://dx.doi.org/S0041-0101(08)00401-7
↑ Schmalhofer WA, Calhoun J, Burrows R, Bailey T, Kohler MG, Weinglass AB, Kaczorowski GJ, Garcia ML, Koltzenburg M, Priest BT. ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Mol Pharmacol. 2008 Nov;74(5):1476-84. doi: 10.1124/mol.108.047670. Epub 2008 Aug, 26. PMID:18728100 doi:http://dx.doi.org/10.1124/mol.108.047670
↑ Lawrence N, Wu B, Ligutti J, Cheneval O, Agwa AJ, Benfield AH, Biswas K, Craik DJ, Miranda LP, Troeira Henriques S, Schroeder CI. Peptide-membrane interactions affect the inhibitory potency and selectivity of spider toxins ProTx-II and GpTx-1. ACS Chem Biol. 2018 Dec 3. doi: 10.1021/acschembio.8b00989. PMID:30507158 doi:http://dx.doi.org/10.1021/acschembio.8b00989

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6mk4"

Categories: Large Structures | Thrixopelma pruriens | Schroeder CI

@@ Line 1: / Line 1: @@
 ==Solution NMR structure of spider toxin analogue [E17K]ProTx-II==
-<StructureSection load='6mk4' size='340' side='right'caption='[[6mk4]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='6mk4' size='340' side='right'caption='[[6mk4]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6mk4]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MK4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MK4 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6mk4]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Thrixopelma_pruriens Thrixopelma pruriens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MK4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MK4 FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6mk4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mk4 OCA], [http://pdbe.org/6mk4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mk4 RCSB], [http://www.ebi.ac.uk/pdbsum/6mk4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mk4 ProSAT]</span></td></tr>
+</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6mk4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mk4 OCA], [https://pdbe.org/6mk4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mk4 RCSB], [https://www.ebi.ac.uk/pdbsum/6mk4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mk4 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/TXPR2_THRPR TXPR2_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.<ref>PMID:12475222</ref> <ref>PMID:17087985</ref> <ref>PMID:17339321</ref> <ref>PMID:18156314</ref> <ref>PMID:18657562</ref> <ref>PMID:18728100</ref>
+[https://www.uniprot.org/uniprot/TXPR2_THRPR TXPR2_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.<ref>PMID:12475222</ref> <ref>PMID:17087985</ref> <ref>PMID:17339321</ref> <ref>PMID:18156314</ref> <ref>PMID:18657562</ref> <ref>PMID:18728100</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 22: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Schroeder, C I]]
+[[Category: Thrixopelma pruriens]]
-[[Category: Peptide-membrane interaction]]
+[[Category: Schroeder CI]]
-[[Category: Protx-ii analogue]]
-[[Category: Spider toxin]]
-[[Category: Toxin]]
-[[Category: Voltage-sensitive sodium channel]]

6mk4

From Proteopedia

Revision as of 10:54, 14 June 2023

Solution NMR structure of spider toxin analogue [E17K]ProTx-II

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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