Ligand-Induced Conformational Change in the α7 Nicotinic Receptor Ligand Binding Domain

Abstract

Molecular dynamics simulations of a homology model of the ligand binding domain of the alpha7 nicotinic receptor are conducted with a range of bound ligands to induce different conformational states. Four simulations of 15 ns each are run with no ligand, antagonist d-tubocurarine (dTC), agonist acetylcholine (ACh), and agonist ACh with potentiator Ca(2+), to give insight into the conformations of the active and inactive states of the receptor and suggest the mechanism for conformational change. The main structural factor distinguishing the active and inactive states is that a more open, symmetric arrangement of the five subunits arises for the two agonist simulations, whereas a more closed and asymmetric arrangement results for the apo and dTC cases. Most of the difference arises in the lower portion of the ligand binding domain near its connection to the adjacent transmembrane domain. The transfer of the more open state to the transmembrane domain could then promote ion flow through the channel. Variation in how subunits pack together with no ligand bound appears to give rise to asymmetry in the apo case. The presence of dTC expands the receptor but induces rotations in alternate directions in adjacent subunits that lead to an asymmetric arrangement as in the apo case. Ca(2+) appears to promote a slightly greater expansion in the subunits than ACh alone by stabilizing the C-loop and ACh positions. Although the simulations are unlikely to be long enough to view the full conformational changes between open and closed states, a collection of different motions at a range of length scales are observed that are likely to participate in the conformational change.

Structural Link between γ-Aminobutyric Acid Type A (GABAA) Receptor Agonist Binding Site and Inner β-Sheet Governs Channel Activation and Allosteric Drug Modulation

“…7A, Table 1). These data are consistent with structural and molecular dynamic studies (1,3,4,(33)(34)(35) in the pLGIC family that indicate asymmetric subunit motions in the extracellular domain help power agonist-mediated gating. Recently, photochemical cleavage of the ␣-subunit GABA A R linker was shown to disrupt GABA activation (36).…”

Charged Residues in the α1and β2Pre-M1 Regions Involved in GABAAReceptor Activation

“…It physically links loop C of the binding site to the membrane domain. Structural studies (Unwin et al, 2002;Celie et al, 2004) as well as molecular dynamic simulations (Henchman et al, 2005) reveal that agonist binding promotes movement of loop C inward to cap the binding site. We predict that this capping movement is propagated to the channel transmembrane domain by the pre-M1 region.…”

Non-Agonist-Binding Subunit Interfaces Confer Distinct Functional Signatures to the Alternate Stoichiometries of the 4 2 Nicotinic Receptor: An 4- 4 Interface Is Required for Zn2+ Potentiation

“…␣4 H195 was selected as a target because the equivalent histidine (␣4 H162 ) in the rat ␣4␤4 receptor was identified previously as a site involved in Zn 2ϩ potentiation (Hsiao et al, 2006) and also because this residue is located in loop F, which is a flexible loop (Szarecka et al, 2007) that may interact with the adjacent subunit in the non-ACh-binding interface. In the ␣4(ϩ)/␣4(Ϫ) interface of the (␣4) 3 (␤2) 2 receptor, ␣4(Ϫ) E92 in loop D and ␣4(ϩ) D217 and ␣4(ϩ) D218 in loop C, which is a very flexible loop as evident from x-ray crystal structures (Hansen et al, 2005) and molecular dynamics studies (Henchman et al, 2003(Henchman et al, , 2005, were identified that could form part of the binding site. In the ␤2(ϩ)/ ␣4(Ϫ) interface of the (␣4) 2 (␤2) 3 receptor, ␤2(ϩ) E224 was selected using this approach.…”