title: Capturing state-dependent dynamic events of GABAA-receptors: a microscopic look into the structural and functional insights.
abstract: The γ-amino butyric acid type A receptors (GABAA-Rs) are the key players in the mammalian brain that meditate fast inhibitory neurotransmission events. The structural integrity of these ligand-gated ion channel controls chloride ion permeability, which in turn monitors important pharmacological functions. Despite ample studies on GABAA-Rs, there was a need for a study on full-length receptor structures, devoted to track structure-function correlations based on their dynamic behavior consideration. We have employed molecular dynamics simulations accompanied by other biophysical methods to shed light on sequential and unaddressed questions like How GABAA-R structure facilitates the entry of GABA molecules at its two orthosteric binding sites? After entry, what structural features and changes monitor site-wise GABA binding differences? In the same context, what are the roles and responsibilities of loops such as C and F? On physiologically relevant time scales, how open to close state transition occurs? How salt bridges such as E155-R207 and E153-R207 maintain state-dependent C-loop structures? In an attempt, our simulation study unravels the complete course of GABA binding-unbinding pathway. This provides us with the relevant understanding of state-dependent dynamic events of GABAA-Rs.
authors.affiliation: a Structural Biology and Bioinformatics Division , CSIR - Indian Institute of Chemical Biology , Kolkata 700032 , India.
authors.forename: Pavan V
authors.initials: PV
authors.lastname: Payghan
authors.affiliation: a Structural Biology and Bioinformatics Division , CSIR - Indian Institute of Chemical Biology , Kolkata 700032 , India.
authors.forename: Indrani
authors.initials: I
authors.lastname: Bera
authors.affiliation: b Computational Science Division , Saha Institute of Nuclear Physics , Kolkata 700 064 , India.
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Bhattacharyya
authors.affiliation: a Structural Biology and Bioinformatics Division , CSIR - Indian Institute of Chemical Biology , Kolkata 700032 , India.
authors.forename: Nanda
authors.initials: N
authors.lastname: Ghoshal
mesh_terms: D001665:Binding Sites; D006860:Hydrogen Bonding; D015640:Ion Channel Gating; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D055550:Protein Stability; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D021122:Protein Subunits; D011963:Receptors, GABA-A
keywords: GABA; GABAA-Receptor; Inhibitory PostSynaptic Currents; molecular dynamics simulations; pentameric ligand-gated ion channel