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

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• 作者：R. S. K. Vijayan ; Neha Trivedi ; Sudipendra Nath Roy ; Indrani Bera ; Prabu Manoharan ; Pavan V. Payghan ; Dhananjay Bhattacharyya ; Nanda Ghoshal
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：52
• 期：11
• 页码：2958-2969
• 全文大小：680K
• 年卷期：v.52,no.11(November 26, 2012)
• ISSN：1549-960X

文摘

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 GABA_A 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 GABA_A was carried out using their respective templates. The ability of induced fit docking in breaking the critical inter residue salt bridge (Glu155尾₂ and Arg207尾₂) 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^{鈥?/sup> ion in the open state and closed state; What structural changes regulate channel gating. A 鈥淭wist to Turn鈥?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 GABA_A ion channel. The modeled structures presented herein not only reveal the structurally distinct conformational states of the GABA_A ion channel but also explain the biophysical difference between the respective states.}