Functional organization and conformational dynamics of the nicotinic receptor: a plausible structural interpretation of myasthenic mutations

Abstract

To understand the structural causes of myasthenic mutations, molecular models of the nicotinic acetycholine receptor were first constructed. Then, the gating transition between resting and open conformation was investigated in silico by normal mode analysis using a physically meaningful description of protein flexibility. This analysis revealed a global quaternary twist motion that opens the ion pore. Second, it was found that most (24/27) of the spontaneous mutations known to cause congenital myasthenia (and autosomal dominant nocturnal frontal lobe epilepsy) are located either at the interface between subunits or, within a given subunit, at the interface between rigid blocks. These interfaces are modified significantly by the twist mode together with significant changes of the tertiary organization of the subunits. These data provide a qualitative interpretation of the molecular phenotype of pathological mutations responsible for congenital myasthenia.