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

Cecilia Bouzat, Fernanda Gumilar, Guillermo Spitzmaul, Hai-Long Wang, Diego Rayes, Scott B. Hansen, Palmer Taylor and Steven M. Sine ()
Additional contact information
Cecilia Bouzat: UNS-CONICET
Fernanda Gumilar: UNS-CONICET
Guillermo Spitzmaul: UNS-CONICET
Hai-Long Wang: Mayo Clinic College of Medicine
Diego Rayes: UNS-CONICET
Scott B. Hansen: University of California, San Diego
Palmer Taylor: University of California, San Diego
Steven M. Sine: Mayo Clinic College of Medicine

Nature, 2004, vol. 430, issue 7002, 896-900

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

Date: 2004
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DOI: 10.1038/nature02753

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