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

被引:236
作者
Bouzat, C
Gumilar, F
Spitzmaul, G
Wang, HL
Rayes, D
Hansen, SB
Taylor, P
Sine, SM [1 ]
机构
[1] Mayo Clin Coll Med, Dept Physiol & Biomed Engn, Receptor Biol Lab, Rochester, MN 55905 USA
[2] Univ Nacl Sur, CONICET, Inst Invest Bioquim, RA-8000 Bahia Blanca, Buenos Aires, Argentina
[3] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1038/nature02753
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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(1) and pore domains(2), 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(1), 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.
引用
收藏
页码:896 / 900
页数:5
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