Coupling of agonist binding to channel gating in an ACh-binding protein linked to ion channel

C BOUZAT; F. GUMILAR,; G. SPITZMAUL; H.L. WANG; D. RAYES; S. HANSEN; P. TAYLOR; SINE, S

NATURE

Nature Publishing Group

Año: 2004 vol. 430 p. 896 - 900

0028-0836

Neurotransmitter receptors from the Cys-loop superfamily couple binding of agonist to opening of an intrinsic ion pore in the ultimate step in rapid synaptic transmission. Atomic resolution structural data recently emerged for individual binding1 and pore domains2, but how they are linked into a functional unit remains unknown. Here we identify structural requirements for functionally coupling the two domains by combining acetylcholine binding protein (AChBP), whose structure was determined at atomic resolution1, with the pore domain from the serotonin type-3A receptor (5-HT3A). Only when amino acid sequences of three loops in AChBP are changed to their 5-HT3A counterparts does ACh (i) bind with low affininity characteristic of activatible receptors and (ii) trigger opening of the ion pore. Thus functional coupling requires structural compatibility at the interface of the binding and pore domains. Structural modeling reveals a network of interacting loops between binding and pore domains that mediates this allosteric coupling process.