A C-terminally amidated analogue of ShK is a potent and selective blocker of the voltage-gated potassium channel Kv1.3.
ShK, a 35-residue peptide from a sea anemone, is a potent blocker of potassium channels. Here we describe a new ShK analogue with an additional C-terminus Lys residue and amide. ShK-K-amide is a potent blocker of Kv1.3 and, in contrast to ShK and ShK-amide, is selective for Kv1.3. To understand this selectivity, we created complexes of ShK-K-amide with Kv1.3 and Kv1.1 using docking and molecular dynamics simulations, then performed umbrella sampling simulations to construct the potential of mean force of the ligand and calculate the corresponding binding free energy for the most stable configuration. The results agree well with experimental data.
Peptides International, 11621 Electron Drive, Louisville, KY 40299, USA.
Michael W
MW
Pennington
M
M
Harunur Rashid
Rajeev B
RB
Tajhya
Christine
C
Beeton
Serdar
S
Kuyucak
Raymond S
RS
Norton
D000465:Algorithms; D000577:Amides / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003064:Cnidarian Venoms / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D051662:Kv1.1 Potassium Channel / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051664:Kv1.3 Potassium Channel / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
D000577:Amides; D003064:Cnidarian Venoms; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; C095391:ShK neurotoxin; D051662:Kv1.1 Potassium Channel