The energy and work of a ligand-gated ion channel.

ABSTRACT: Ligand-gated ion channels are allosteric membrane proteins that isomerize between C(losed) and O(pen) conformations. A difference in affinity for ligands in the two states influences the C?O "gating" equilibrium constant. The energies associated with adult-type mouse neuromuscular nicotinic acetylcholine receptor (AChR) channel gating have been measured by using single-channel electrophysiology. Without ligands, the free energy, enthalpy and entropy of gating are ?G0=+8.4, ?H0=+10.9 and T?S0=+2.5kcal/mol (-100mV, 23°C). Many mutations throughout the protein change ?G0, including natural ones that cause disease. Agonists and most mutations change approximately independently the ground-state energy difference; thus, it is possible to forecast and engineer AChR responses simply by combining perturbations. The free energy of the low?high affinity change for the neurotransmitter at each of two functionally equivalent binding sites is ?GB(ACh)=-5.1kcal/mol. ?GB(ACh) is set mainly by interactions of ACh with just three binding site aromatic groups. For a series of structurally related agonists, there is a correlation between the energies of low- and high-affinity binding, which implies that gating commences with the formation of the low-affinity complex. Brief, intermediate states in binding and gating have been detected. Several proposals for the nature of the gating transition-state energy landscape and the isomerization mechanism are discussed.

SUBMITTER: Auerbach A 

PROVIDER: S-EPMC4407511 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature