Mechanisms of inward-rectifier K+ channel inhibition by tertiapin-Q.
Tertiapin-Q (TPN(Q)) is a derivative of honey bee toxin tertiapin (TPN) whose methionine residue is replaced with a glutamine residue. TPN(Q) inhibits the ROMK1 and GIRK1/4 inward-rectifier K(+) channels with affinities very similar to TPN. However, unlike native TPN, TPN(Q) is nonoxidizable by air. The stability of TPN(Q) allows us to investigate how it interacts with the targeted channels. We found that the interaction between TPN(Q) and the ROMK1 channel is a bimolecular reaction, i.e., one TPN(Q) molecule binds to one channel. The interaction surface in TPN(Q) is primarily formed by its alpha helix rather than the beta sheets with which scorpion toxins form their interaction surface. The mutagenesis studies on both the channel and TPN(Q) together strongly suggest that to block the K(+) pore TPN(Q) plugs its alpha helix into the vestibule of the K(+) pore, while leaving the extended structural portion sticking out of the vestibule into the extracellular media.
Jin
W
W
Department of Physiology, University of Pennsylvania, Philadelphia 19104, USA.
Klem
A M
AM
Lewis
J H
JH
Lu
Z
Z
D000409:Alanine / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001514:Bee Venoms / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D014982:Xenopus laevis
D001514:Bee Venoms; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011994:Recombinant Proteins; C029738:tertiapin; D000409:Alanine