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Modeling the Closed and Open State Conformations of the GABAA Ion Channel - Plausible Structural Insights for Channel Gating

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Title Modeling the Closed and Open State Conformations of the GABAA Ion Channel - Plausible Structural Insights for Channel Gating
 
Creator Vijayan, R. S. K
Trivedi, Neha
Roy, Sudipendra Nath
Bera, Indrani
Manoharan, Prabu
Payghan, Pavan V
Bhattacharyya, Dhananjay
Ghoshal, Nanda
 
Subject Structural Biology & Bioinformatics
 
Description Recent disclosure of high resolution crystal structures of Gloeobacter violaceus (GLIC) in open state and Erwinia chrysanthemii (ELIC) in closed state provides newer
avenues to advance our knowledge and understanding of the
physiologically and pharmacologically important ionotropic
GABAA ion channel. The present modeling study envisions
understanding the complex molecular transitions involved in
ionic conductance, which were not evident in earlier disclosed homology models. In particular, emphasis was put on understanding the structural basis of gating, gating transition from the closed to the open state on an atomic scale. Homology modeling of two different physiological states of GABAA was carried out using their respective templates. The ability of induced fit docking in breaking the critical inter residue salt bridge (Glu155β2 and Arg207β2) upon endogenous GABA docking reflects the perceived side chain rearrangements that occur at the
orthosteric site and consolidate the quality of the model. Biophysical calculations like electrostatic mapping, pore radius calculation, ion solvation profile, and normal-mode analysis (NMA) were undertaken to address pertinent questions like the following: How the change in state of the ion channel alters the electrostatic environment across the lumen; How accessible is the Cl− ion in the open state and closed state; What structural changes regulate channel gating. A “Twist to Turn” global motion evinced at the quaternary level accompanied by tilting and rotation of the M2 helices along the membrane normal rationalizes the
structural transition involved in gating. This perceived global motion hints toward a conserved gating mechanism among pLGIC. To paraphrase, this modeling study proves to be a reliable framework for understanding the structure function relationship of the hitherto unresolved GABAA ion channel. The modeled structures presented herein not only reveal the structurally distinct conformational states of the GABAA ion channel but also explain the biophysical difference between the respective states.
 
Date 2012
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/2275/1/JOURNAL_OF_CHEMICAL_INFORMATION_AND_MODELING__V._52__(_11_)_2958%2D2969_;2012.pdf
Vijayan, R. S. K and Trivedi, Neha and Roy, Sudipendra Nath and Bera, Indrani and Manoharan, Prabu and Payghan, Pavan V and Bhattacharyya, Dhananjay and Ghoshal, Nanda (2012) Modeling the Closed and Open State Conformations of the GABAA Ion Channel - Plausible Structural Insights for Channel Gating. Journal of Chemical Information and Modeling, 52 (11). pp. 2956-2969.
 
Relation http://dx.doi.org/10.1021/ci300189a
http://www.eprints.iicb.res.in/2275/