Capturing state-dependent dynamic events of GABAA-receptors: a microscopic look into the structural and functional insights
| Autor: | Indrani Bera, Nanda Ghoshal, Pavan V. Payghan, Dhananjay Bhattacharyya |
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| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine Protein Conformation Context (language use) Plasma protein binding Molecular Dynamics Simulation Neurotransmission Ligands Inhibitory postsynaptic potential Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Protein structure Structural Biology Receptor Molecular Biology Ion channel Binding Sites Protein Stability Chemistry GABAA receptor Hydrogen Bonding General Medicine Receptors GABA-A Molecular Docking Simulation Protein Subunits 030104 developmental biology Biochemistry Protein Multimerization Ion Channel Gating Neuroscience 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Journal of Biomolecular Structure and Dynamics. 34:1818-1837 |
| ISSN: | 1538-0254 0739-1102 |
| DOI: | 10.1080/07391102.2015.1094410 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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