1. Instituto de Investigaciones Bioquimicas, UNS-CONICET, Bahia Blanca 8000, Argentina
2. Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
3. Department of Pharmacology, University of California, San Diego, La Jolla, California 92093-0636, USA

Correspondence to: Steven M. Sine² Correspondence and requests for materials should be addressed to S. M. S. (Email: sine@mayo.edu).

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-HT_3A) receptor. Only when amino-acid sequences of three loops in ACh-binding protein are changed to their 5-HT_3A 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.

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