Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites

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Abstract

γ-aminobutyric acid receptors (GABA ARs) are vital for controlling excitability in the brain. This is emphasized by the numerous neuropsychiatric disorders that result following receptor dysfunction. A critical component of most native GABA ARs is the α subunit. Its transmembrane domain is the target for many modulators, including endogenous brain neurosteroids that impact on anxiety, stress and depression, and for therapeutic drugs such as general anaesthetics. To understand the basis for modulating GABA AR function, high-resolution structures are required. Here we present the first atomic structures of a GABA AR chimera at 2.8Å resolution, including those bound with potentiating and inhibitory neurosteroids. These define new allosteric binding sites for these modulators that are associated with the α-subunit transmembrane domain. Our findings will enable neurosteroids to be exploited for therapeutic drug design to regulate GABA ARs in neurological disorders.

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PROPKA3: Consistent Treatment of Internal and Surface Residues in Empirical pKa Predictions.

Mats H. M. Olsson, Chresten Søndergaard, Michal Rostkowski … (2011)

In this study, we have revised the rules and parameters for one of the most commonly used empirical pKa predictors, PROPKA, based on better physical description of the desolvation and dielectric response for the protein. We have introduced a new and consistent approach to interpolate the description between the previously distinct classifications into internal and surface residues, which otherwise is found to give rise to an erratic and discontinuous behavior. Since the goal of this study is to lay out the framework and validate the concept, it focuses on Asp and Glu residues where the protein pKa values and structures are assumed to be more reliable. The new and improved implementation is evaluated and discussed; it is found to agree better with experiment than the previous implementation (in parentheses): rmsd = 0.79 (0.91) for Asp and Glu, 0.75 (0.97) for Tyr, 0.65 (0.72) for Lys, and 1.00 (1.37) for His residues. The most significant advance, however, is in reducing the number of outliers and removing unreasonable sensitivity to small structural changes that arise from classifying residues as either internal or surface.

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Lipid14: The Amber Lipid Force Field

Callum Dickson, Benjamin D. Madej, Åge A. Skjevik … (2014)

The AMBER lipid force field has been updated to create Lipid14, allowing tensionless simulation of a number of lipid types with the AMBER MD package. The modular nature of this force field allows numerous combinations of head and tail groups to create different lipid types, enabling the easy insertion of new lipid species. The Lennard-Jones and torsion parameters of both the head and tail groups have been revised and updated partial charges calculated. The force field has been validated by simulating bilayers of six different lipid types for a total of 0.5 μs each without applying a surface tension; with favorable comparison to experiment for properties such as area per lipid, volume per lipid, bilayer thickness, NMR order parameters, scattering data, and lipid lateral diffusion. As the derivation of this force field is consistent with the AMBER development philosophy, Lipid14 is compatible with the AMBER protein, nucleic acid, carbohydrate, and small molecule force fields.

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General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal.

Nicholas Franks (2008)

The mechanisms through which general anaesthetics, an extremely diverse group of drugs, cause reversible loss of consciousness have been a long-standing mystery. Gradually, a relatively small number of important molecular targets have emerged, and how these drugs act at the molecular level is becoming clearer. Finding the link between these molecular studies and anaesthetic-induced loss of consciousness presents an enormous challenge, but comparisons with the features of natural sleep are helping us to understand how these drugs work and the neuronal pathways that they affect. Recent work suggests that the thalamus and the neuronal networks that regulate its activity are the key to understanding how anaesthetics cause loss of consciousness.