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, Steven M. Sine

Research output: Contribution to journalArticle

223 Scopus citations

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 binding and pore domains 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 resolution, 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.

Original languageEnglish (US)
Pages (from-to)896-900
Number of pages5
JournalNature
Volume430
Issue number7002
DOIs
StatePublished - Aug 19 2004

ASJC Scopus subject areas

  • General

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    Bouzat, C., Gumilar, F., Spitzmaul, G., Wang, H. L., Rayes, D., Hansen, S. B., Taylor, P., & Sine, S. M. (2004). Coupling of agonist binding to channel gating in an ACh-binding protein linked to an ion channel. Nature, 430(7002), 896-900. https://doi.org/10.1038/nature02753