Ligand-induced conformational change in the α7 nicotinic receptor ligand binding domain

Richard H. Henchman, Hai Long Wang, Steven M Sine, Palmer Taylor, J. Andrew McCammon

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Molecular dynamics simulations of a homology model of the ligand binding domain of the α7 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 Ca2+, 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. Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)2564-2576
Number of pages13
JournalBiophysical Journal
Volume88
Issue number4
DOIs
StatePublished - Apr 2005

Fingerprint

Nicotinic Receptors
Tubocurarine
Ligands
Acetylcholine
Cholinergic Agonists
Molecular Dynamics Simulation
Ions

ASJC Scopus subject areas

  • Biophysics

Cite this

Ligand-induced conformational change in the α7 nicotinic receptor ligand binding domain. / Henchman, Richard H.; Wang, Hai Long; Sine, Steven M; Taylor, Palmer; McCammon, J. Andrew.

In: Biophysical Journal, Vol. 88, No. 4, 04.2005, p. 2564-2576.

Research output: Contribution to journalArticle

Henchman, Richard H. ; Wang, Hai Long ; Sine, Steven M ; Taylor, Palmer ; McCammon, J. Andrew. / Ligand-induced conformational change in the α7 nicotinic receptor ligand binding domain. In: Biophysical Journal. 2005 ; Vol. 88, No. 4. pp. 2564-2576.
@article{2de13e9aa5514326a7227adb7cf9e963,
title = "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 α7 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 Ca2+, 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. Ca2+ 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.",
author = "Henchman, {Richard H.} and Wang, {Hai Long} and Sine, {Steven M} and Palmer Taylor and McCammon, {J. Andrew}",
year = "2005",
month = "4",
doi = "10.1529/biophysj.104.053934",
language = "English (US)",
volume = "88",
pages = "2564--2576",
journal = "Biophysical Journal",
issn = "0006-3495",
publisher = "Biophysical Society",
number = "4",

}

TY - JOUR

T1 - Ligand-induced conformational change in the α7 nicotinic receptor ligand binding domain

AU - Henchman, Richard H.

AU - Wang, Hai Long

AU - Sine, Steven M

AU - Taylor, Palmer

AU - McCammon, J. Andrew

PY - 2005/4

Y1 - 2005/4

N2 - Molecular dynamics simulations of a homology model of the ligand binding domain of the α7 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 Ca2+, 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. Ca2+ 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.

AB - Molecular dynamics simulations of a homology model of the ligand binding domain of the α7 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 Ca2+, 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. Ca2+ 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.

UR - http://www.scopus.com/inward/record.url?scp=18744410192&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=18744410192&partnerID=8YFLogxK

U2 - 10.1529/biophysj.104.053934

DO - 10.1529/biophysj.104.053934

M3 - Article

C2 - 15665135

AN - SCOPUS:18744410192

VL - 88

SP - 2564

EP - 2576

JO - Biophysical Journal

JF - Biophysical Journal

SN - 0006-3495

IS - 4

ER -