Structure of the BgK-Kv1.1 complex based on distance restraints identified by double mutant cycles. Molecular basis for convergent evolution of Kv1 channel blockers.
A structural model of BgK, a sea anemone toxin, complexed with the S5-S6 region of Kv1.1, a voltage-gated potassium channel, was determined by flexible docking under distance restraints identified by a double mutant cycles approach. This structure provides the molecular basis for identifying the major determinants of the BgK-Kv1.1 channel interactions involving the BgK dyad residues Lys(25) and Tyr(26). These interactions are (i) electrostatic interactions between the extremity of Lys(25) side chain and carbonyl oxygen atoms of residues from the channel selectivity filter that may be strengthened by solvent exclusion provided by (ii) hydrophobic interactions involving BgK residues Tyr(26) and Phe(6) and Kv1.1 residue Tyr(379) whose side chain protrudes in the channel vestibule. In other Kv1 channel-BgK complexes, these interactions are likely to be conserved, implicating both conserved and variable residues from the channels. The data suggest that the conservation in sea anemone and scorpion potassium channel blockers of a functional dyad composed of a lysine, and a hydrophobic residue reflects their use of convergent binding solutions based on a crucial interplay between these important conserved interactions.
Département d'Ingénierie et d'Etudes des Protéines, CEA Saclay, 91191 Gif sur Yvette cedex, France. bgilquin@cea.fr
Bernard
B
Gilquin
Judith
J
Racapé
Anja
A
Wrisch
Violeta
V
Visan
Alain
A
Lecoq
Stephan
S
Grissmer
André
A
Ménez
Sylvaine
S
Gasparini
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D003064:Cnidarian Venoms / Q000737:chemistry* / Q000494:pharmacology; D051662:Kv1.1 Potassium Channel; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000737:chemistry* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D051381:Rats; D012615:Sea Anemones; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D003064:Cnidarian Venoms; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C104455:toxin BgK; D051662:Kv1.1 Potassium Channel