Tuning Scorpion Toxin Selectivity: Switching From KV1.1 to KV1.3 Article Swipe
Andrei M. Gigolaev
,
Alexey I. Kuzmenkov
,
Steve Peigneur
,
Valentin М. Tabakmakher
,
Ernesto Lopes Pinheiro-Júnior
,
Anton O. Chugunov
,
Roman G. Efremov
,
Jan Tytgat
,
Alexander A. Vassilevski
·
YOU?
·
· 2020
· Open Access
·
· DOI: https://doi.org/10.3389/fphar.2020.01010
YOU?
·
· 2020
· Open Access
·
· DOI: https://doi.org/10.3389/fphar.2020.01010
Voltage-gated potassium channels (KVs) perform vital physiological functions and are targets in different disorders ranging from ataxia and arrhythmia to autoimmune diseases. An important issue is the search for and production of selective ligands of these channels. Peptide toxins found in scorpion venom named KTx excel in both potency and selectivity with respect to some potassium channel isoforms, which may present only minute differences in their structure. Despite several decades of research the molecular determinants of KTx selectivity are still poorly understood. Here we analyze MeKTx13-3 (Kalium ID: α-KTx 3.19) from the lesser Asian scorpion Mesobuthus eupeus, a high-affinity KV1.1 blocker (IC50 ~2 nM); it also affects KV1.2 (IC50 ~100 nM), 1.3 (~10 nM) and 1.6 (~60 nM). By constructing computer models of its complex with KV1.1-1.3 channels we identify specific contacts between the toxin and the three isoforms. We then perform mutagenesis to disturb the identified contacts with KV1.1 and 1.2 and produce recombinant MeKTx13-3_AAAR, which differs by four amino acid residues from the parent toxin. As predicted by the modeling, this derivative shows decreased activity on KV1.1 (IC50 ~550 nM) and 1.2 (~200 nM). It also has diminished activity on KV1.6 (~1500 nM) but preserves KV1.3 affinity as measured using the voltage-clamp technique on mammalian channels expressed in Xenopus oocytes. In effect, we convert a selective KV1.1 ligand into a new specific KV1.3 ligand. MeKTx13-3 and its derivatives are attractive tools to study the structure-function relationship in potassium channel blockers.
Related Topics
Concepts
Potassium channel
Chemistry
Scorpion toxin
Xenopus
Toxin
Scorpion Venoms
Selectivity
Ligand (biochemistry)
Gene isoform
Venom
IC50
Biophysics
Biochemistry
Pharmacology
Scorpion
Biology
Receptor
In vitro
Gene
Catalysis
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.3389/fphar.2020.01010
- OA Status
- gold
- Cited By
- 13
- References
- 63
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W3039518918
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W3039518918Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.3389/fphar.2020.01010Digital Object Identifier
- Title
-
Tuning Scorpion Toxin Selectivity: Switching From KV1.1 to KV1.3Work title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2020Year of publication
- Publication date
-
2020-07-07Full publication date if available
- Authors
-
Andrei M. Gigolaev, Alexey I. Kuzmenkov, Steve Peigneur, Valentin М. Tabakmakher, Ernesto Lopes Pinheiro-Júnior, Anton O. Chugunov, Roman G. Efremov, Jan Tytgat, Alexander A. VassilevskiList of authors in order
- Landing page
-
https://doi.org/10.3389/fphar.2020.01010Publisher landing page
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://doi.org/10.3389/fphar.2020.01010Direct OA link when available
- Concepts
-
Potassium channel, Chemistry, Scorpion toxin, Xenopus, Toxin, Scorpion Venoms, Selectivity, Ligand (biochemistry), Gene isoform, Venom, IC50, Biophysics, Biochemistry, Pharmacology, Scorpion, Biology, Receptor, In vitro, Gene, CatalysisTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
13Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 4, 2024: 1, 2023: 3, 2022: 1, 2021: 4Per-year citation counts (last 5 years)
- References (count)
-
63Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.toxin. | 166 |
| abstract_inverted_index.toxins | 38 |
| abstract_inverted_index.α-KTx | 88 |
| abstract_inverted_index.(Kalium | 86 |
| abstract_inverted_index.Despite | 67 |
| abstract_inverted_index.Peptide | 37 |
| abstract_inverted_index.affects | 106 |
| abstract_inverted_index.analyze | 84 |
| abstract_inverted_index.between | 132 |
| abstract_inverted_index.blocker | 100 |
| abstract_inverted_index.channel | 56, 240 |
| abstract_inverted_index.complex | 124 |
| abstract_inverted_index.convert | 215 |
| abstract_inverted_index.decades | 69 |
| abstract_inverted_index.differs | 157 |
| abstract_inverted_index.disturb | 144 |
| abstract_inverted_index.effect, | 213 |
| abstract_inverted_index.ligand. | 225 |
| abstract_inverted_index.ligands | 33 |
| abstract_inverted_index.perform | 4, 141 |
| abstract_inverted_index.potency | 48 |
| abstract_inverted_index.present | 60 |
| abstract_inverted_index.produce | 153 |
| abstract_inverted_index.ranging | 14 |
| abstract_inverted_index.respect | 52 |
| abstract_inverted_index.several | 68 |
| abstract_inverted_index.targets | 10 |
| abstract_inverted_index.activity | 176, 190 |
| abstract_inverted_index.affinity | 198 |
| abstract_inverted_index.channels | 2, 127, 207 |
| abstract_inverted_index.computer | 120 |
| abstract_inverted_index.contacts | 131, 147 |
| abstract_inverted_index.identify | 129 |
| abstract_inverted_index.measured | 200 |
| abstract_inverted_index.oocytes. | 211 |
| abstract_inverted_index.research | 71 |
| abstract_inverted_index.residues | 162 |
| abstract_inverted_index.scorpion | 41, 94 |
| abstract_inverted_index.specific | 130, 223 |
| abstract_inverted_index.MeKTx13-3 | 85, 226 |
| abstract_inverted_index.blockers. | 241 |
| abstract_inverted_index.channels. | 36 |
| abstract_inverted_index.decreased | 175 |
| abstract_inverted_index.different | 12 |
| abstract_inverted_index.diseases. | 21 |
| abstract_inverted_index.disorders | 13 |
| abstract_inverted_index.expressed | 208 |
| abstract_inverted_index.functions | 7 |
| abstract_inverted_index.important | 23 |
| abstract_inverted_index.isoforms, | 57 |
| abstract_inverted_index.isoforms. | 138 |
| abstract_inverted_index.mammalian | 206 |
| abstract_inverted_index.modeling, | 171 |
| abstract_inverted_index.molecular | 73 |
| abstract_inverted_index.potassium | 1, 55, 239 |
| abstract_inverted_index.predicted | 168 |
| abstract_inverted_index.preserves | 196 |
| abstract_inverted_index.selective | 32, 217 |
| abstract_inverted_index.technique | 204 |
| abstract_inverted_index.arrhythmia | 18 |
| abstract_inverted_index.attractive | 231 |
| abstract_inverted_index.autoimmune | 20 |
| abstract_inverted_index.derivative | 173 |
| abstract_inverted_index.diminished | 189 |
| abstract_inverted_index.identified | 146 |
| abstract_inverted_index.production | 30 |
| abstract_inverted_index.structure. | 66 |
| abstract_inverted_index.derivatives | 229 |
| abstract_inverted_index.differences | 63 |
| abstract_inverted_index.eupeus</i>, | 96 |
| abstract_inverted_index.mutagenesis | 142 |
| abstract_inverted_index.recombinant | 154 |
| abstract_inverted_index.selectivity | 50, 77 |
| abstract_inverted_index.understood. | 81 |
| abstract_inverted_index.constructing | 119 |
| abstract_inverted_index.determinants | 74 |
| abstract_inverted_index.relationship | 237 |
| abstract_inverted_index.<i>Mesobuthus | 95 |
| abstract_inverted_index.Voltage-gated | 0 |
| abstract_inverted_index.high-affinity | 98 |
| abstract_inverted_index.physiological | 6 |
| abstract_inverted_index.voltage-clamp | 203 |
| abstract_inverted_index.<i>Xenopus</i> | 210 |
| abstract_inverted_index.MeKTx13-3_AAAR, | 155 |
| abstract_inverted_index.(IC<sub>50</sub> | 101, 108, 179 |
| abstract_inverted_index.(K<sub>V</sub>s) | 3 |
| abstract_inverted_index.K<sub>V</sub>1.1 | 99, 149, 178, 218 |
| abstract_inverted_index.K<sub>V</sub>1.2 | 107 |
| abstract_inverted_index.K<sub>V</sub>1.3 | 197, 224 |
| abstract_inverted_index.K<sub>V</sub>1.6 | 192 |
| abstract_inverted_index.structure-function | 236 |
| abstract_inverted_index.K<sub>V</sub>1.1-1.3 | 126 |
| cited_by_percentile_year.max | 98 |
| cited_by_percentile_year.min | 89 |
| corresponding_author_ids | https://openalex.org/A5065518722 |
| countries_distinct_count | 2 |
| institutions_distinct_count | 9 |
| corresponding_institution_ids | https://openalex.org/I153845743, https://openalex.org/I4210105571 |
| citation_normalized_percentile.value | 0.69186518 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |