J Chem Inf Model - Modeling the closed and open state conformations of the GABA(A) ion channel--plausible structural insights for channel gating.


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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?(2) and Arg207?(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(-) 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 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.

Resumo Limpo

recent disclosur high resolut crystal structur gloeobact violaceus glic open state erwinia chrysanthemii elic close state provid newer avenu advanc knowledg understand physiolog pharmacolog import ionotrop gabaa ion channel present model studi envis understand complex molecular transit involv ionic conduct evid earlier disclos homolog model particular emphasi put understand structur basi gate gate transit close open state atom scale homolog model two differ physiolog state gabaa carri use respect templat abil induc fit dock break critic inter residu salt bridg glu arg upon endogen gaba dock reflect perceiv side chain rearrang occur orthoster site consolid qualiti model biophys calcul like electrostat map pore radius calcul ion solvat profil normalmod analysi nma undertaken address pertin question like follow chang state ion channel alter electrostat environ across lumen access cl ion open state close state structur chang regul channel gate twist turn global motion evinc quaternari level accompani tilt rotat m helic along membran normal ration structur transit involv gate perceiv global motion hint toward conserv gate mechan among plgic paraphras model studi prove reliabl framework understand structur function relationship hitherto unresolv gabaa ion channel model structur present herein reveal structur distinct conform state gabaa ion channel also explain biophys differ respect state

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