title: BeKm-1 is a HERG-specific toxin that shares the structure with ChTx but the mechanism of action with ErgTx1.
abstract: Peptide toxins with disulfide-stabilized structures have been used as molecular calipers to probe the outer vestibule structure of K channels. We want to apply this approach to the human ether-a-go-go-related gene (HERG) channel, whose outer vestibule is unique in structure and function among voltage-gated K channels. Our focus here is BeKm-1, a HERG-specific peptide toxin that can suppress HERG in the low nM concentration range. Although BeKm-1 shares the three-dimensional scaffold with the well-studied charybdotoxin, the two use different mechanisms in suppressing currents through their target K channels. BeKm-1 binds near, but not inside, the HERG pore, and it is possible that BeKm-1-bound HERG channels can conduct currents although with markedly altered voltage-dependence and kinetics of gating. BeKm-1 and ErgTx1 differ in three-dimensional scaffold, but the two share mechanism of action and have overlapping binding sites on the HERG channel. For both, residues in the middle of the S5-P linker (the putative 583-597 helix) and residues at the pore entrance are critical for binding, although specific contact points vary between the two. Toxin foot printing using BeKm-1 and ErgTx1 will likely provide complementary information about the unique outer vestibule structure of the HERG channel.
authors.affiliation: Department of Physiology, Virginia Commonwealth University, Richmond 23298, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.forename: Yuliya V
authors.initials: YV
authors.lastname: Korolkova
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Grishin
authors.forename: Gea-Ny
authors.initials: GN
authors.lastname: Tseng
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D027682:Cation Transport Proteins; D002478:Cells, Cultured; D018999:Charybdotoxin / Q000737:chemistry*; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D016062:Porosity; D015221:Potassium Channels / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D011485:Protein Binding; D011487:Protein Conformation; D015203:Reproducibility of Results; D012604:Scorpion Venoms / Q000737:chemistry* / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014982:Xenopus laevis
chemical_list: C425305:BeKm-1 toxin; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D012604:Scorpion Venoms; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C118951:ergotoxin, Centruroides noxius; D018999:Charybdotoxin