Homology Model of the GABAA Receptor Examined Using Brownian Dynamics
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O’Mara, Megan; Cromer, Brett; Parker, Michael; Chung, Shin-Ho
Description
We have developed a homology model of the GABAA receptor, using the subunit combination of α1β2γ2, the most prevalent type in the mammalian brain. The model is produced in two parts: the membrane-embedded channel domain and the extracellular N-terminal domain. The pentameric transmembrane domain model is built by modeling each subunit by homology with the equivalent subunit of the heteropentameric acetylcholine receptor transmembrane domain. This segment is then joined with the extracellular...[Show more]
dc.contributor.author | O’Mara, Megan | |
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dc.contributor.author | Cromer, Brett | |
dc.contributor.author | Parker, Michael | |
dc.contributor.author | Chung, Shin-Ho | |
dc.date.accessioned | 2016-03-23T00:00:35Z | |
dc.date.available | 2016-03-23T00:00:35Z | |
dc.identifier.issn | 0006-3495 | |
dc.identifier.uri | http://hdl.handle.net/1885/100865 | |
dc.description.abstract | We have developed a homology model of the GABAA receptor, using the subunit combination of α1β2γ2, the most prevalent type in the mammalian brain. The model is produced in two parts: the membrane-embedded channel domain and the extracellular N-terminal domain. The pentameric transmembrane domain model is built by modeling each subunit by homology with the equivalent subunit of the heteropentameric acetylcholine receptor transmembrane domain. This segment is then joined with the extracellular domain built by homology with the acetylcholine binding protein. The all-atom model forms a wide extracellular vestibule that is connected to an oval chamber near the external surface of the membrane. A narrow, cylindrical transmembrane channel links the outer segment of the pore to a shallow intracellular vestibule. The physiological properties of the model so constructed are examined using electrostatic calculations and Brownian dynamics simulations. A deep energy well of ∼80 kT accommodates three Cl− ions in the narrow transmembrane channel and seven Cl− ions in the external vestibule. Inward permeation takes place when one of the ions queued in the external vestibule enters the narrow segment and ejects the innermost ion. The model, when incorporated into Brownian dynamics, reproduces key experimental features, such as the single-channel current-voltage-concentration profiles. Finally, we simulate the γ2 K289M epilepsy inducing mutation and examine Cl− ion permeation through the mutant receptor. | |
dc.description.sponsorship | This work was supported by grants from the Australian Research Council and the National Health and Medical Research Council of Australia. | |
dc.publisher | Biophysical Society | |
dc.rights | © 2005 by the Biophysical Society | |
dc.source | Biophysical Journal | |
dc.subject | acetylcholine | |
dc.subject | amino acid sequence | |
dc.subject | animals | |
dc.subject | biophysics | |
dc.subject | brain | |
dc.subject | chlorides | |
dc.subject | chlorine | |
dc.subject | computer simulation | |
dc.subject | dose-response relationship, drug | |
dc.subject | ions | |
dc.subject | ligands | |
dc.subject | lymnaea | |
dc.subject | models, molecular | |
dc.subject | models, statistical | |
dc.subject | models, theoretical | |
dc.subject | molecular sequence data | |
dc.subject | mutagenesis, site-directed | |
dc.subject | mutation | |
dc.subject | protein binding | |
dc.subject | protein conformation | |
dc.subject | protein structure, tertiary | |
dc.subject | receptors, cholinergic | |
dc.subject | receptors, gaba-a | |
dc.subject | static electricity | |
dc.title | Homology Model of the GABAA Receptor Examined Using Brownian Dynamics | |
dc.type | Journal article | |
local.description.notes | Imported from ARIES | |
local.description.refereed | Yes | |
local.identifier.citationvolume | 88 | |
dc.date.issued | 2005 | |
local.identifier.absfor | 029901 | |
local.identifier.ariespublication | MigratedxPub11731 | |
local.publisher.url | http://www.elsevier.com/ | |
local.type.status | Published Version | |
local.contributor.affiliation | O'Mara, Megan, College of Physical and Mathematical Sciences, CPMS Research School of Physics and Engineering, Department of Theoretical Physics, The Australian National University | |
local.contributor.affiliation | Cromer, Brett A, St Vincent's Institute, Biota Str Biol Lab, Australia | |
local.contributor.affiliation | Parker, Michael William, St Vincent's Institute, Biota Str Biol Lab, Australia | |
local.contributor.affiliation | Chung, Shin-Ho, College of Physical and Mathematical Sciences, CPMS Research School of Physics and Engineering, Department of Theoretical Physics, The Australian National University | |
local.bibliographicCitation.issue | 5 | |
local.bibliographicCitation.startpage | 3286 | |
local.bibliographicCitation.lastpage | 3299 | |
local.identifier.doi | 10.1529/biophysj.104.051664 | |
dc.date.updated | 2016-06-14T08:37:05Z | |
local.identifier.scopusID | 2-s2.0-17844374081 | |
Collections | ANU Research Publications |
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