Using molecular dynamics to elucidate the structural basis for function in pLGICs

Akabas, Myles H.

doi:10.1073/pnas.1316157110

Cited by 7 publications

(6 citation statements)

References 23 publications

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“…We explored this hypothesis in the models. We found that in the Gly5 simulation, the mean distance between T54 and L274 Cα (∼5.5 Å vs 4.9 Å in ref 50) was compatible with the ability to form a disulfide bond (Figure 4). The Apo, Gly3, and Gly3′ simulations adopted positions in which the two residues were slightly further apart, but perhaps the most startling divergence was in the Stry simulation, in which this distance is increased by approximately 4 Å over the course of the simulation (Figure 4B), suggesting that the presence of an antagonist could move the receptor into a conformational state distinct from that induced by agonists from the apo conformation.…”

Section: And Other Prokaryoticmentioning

confidence: 70%

“…The smaller change for the latter is reasonable considering the initial model was built using GluCl as the template and represents an open or desensitized state. 22,50 However, closer inspection revealed that the strychnine-bound simulation behaves quite differently from all the other simulations. Of central importance for Cys-loop receptor activation is the movement of loop C. We thus explored the opening and closing of loop C (Figure 3) via the definition of a distance between Cα of Q203 in loop C and Cα of S40, which is positioned on a β sheet (β1 in Figure 1B) at the rear of the binding pocket.…”

Section: Biochemistrymentioning

confidence: 97%

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Agonist and Antagonist Binding in Human Glycine Receptors

Hurdiss

Greiner

et al. 2014

Biochemistry

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The human glycine receptor (hGlyR) is an anion-permeable ligand-gated channel that is part of a larger superfamily of receptors called the Cys-loop family. hGlyRs are particularly amenable to single-channel recordings, thus making them a model experimental system for understanding the Cys-loop receptor family in general. Understanding the relationship between agonist binding and efficacy in Cys-loop receptors should improve our future prospects for making specific agonists or antagonists. However, at present, there is no high-resolution structure for the complete hGlyR, and thus, modeling is needed to provide a physical framework on which to interpret single-channel data. The structure of the glutamate-gated chloride channel from Caenorhabditis elegans shows a much higher level of sequence identity to human hGlyR than previous templates such as AChBP or the bacterial channels, GLIC and ELIC. Thus, we constructed a model of the hGlyR and validated it against previously reported mutagenesis data. We used molecular dynamics to refine the model and to explore binding of both an agonist (glycine) and an antagonist (strychnine). The model shows excellent agreement with previous data but also suggests some unique features: (i) a water molecule that forms part of the binding site and allows us to account for some previous results that were difficult to reconcile, (ii) an interaction of the glycine agonist with S129, and (iii) an effect from E211, both of which we confirmed with new site-directed mutagenesis and patch clamp recordings. Finally, examination of the simulations suggests that strychnine binding induces movement to a conformational state distinct from the glycine-bound or apo state, not only within the ligand-binding domain but also in the transmembrane domain.

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Section: And Other Prokaryoticmentioning

confidence: 70%

Section: Biochemistrymentioning

confidence: 97%

Agonist and Antagonist Binding in Human Glycine Receptors

Hurdiss

Greiner

et al. 2014

Biochemistry

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“…However, they possess distinct M2 conformations as indicated by the rotation angle (φ), perhaps reflective of their distinct states: antagonist/closed and resting/closed. In group 2 , gly/ivm -GlyR and glu/ivm -GluCl share similar pore profiles and M2 conformations, suggesting they represent similar physiological states, perhaps desensitized-like or partially open, low-conductance states 35 . Despite a tighter restriction at the intracellular entrance, the pore properties of the GABA A receptor resemble that of gly/ivm -GlyR.…”

Section: Ion Channel Porementioning

confidence: 99%

Glycine receptor mechanism elucidated by electron cryo-microscopy

Lü

et al. 2015

Nature

383

613

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Summary The strychnine-sensitive glycine receptor (GlyR) mediates inhibitory synaptic transmission in the spinal cord and brainstem and is linked to neurological disorders including autism and hyperekplexia. Understanding of molecular mechanisms and pharmacology of GlyRs has been hindered by a dearth of high-resolution structures. Here we report electron cryo-microscopy structures of the α1 GlyR with strychnine, glycine, or glycine/ivermectin. Strychnine arrests the receptor in an antagonist-bound, closed ion channel state, glycine stabilizes the receptor in an agonist-bound open channel state, and the glycine/ivermectin complex adopts a potentially desensitized or partially open state. Relative to the glycine-bound state, strychnine expands the agonist-binding pocket via outward movement of the C loop, promotes rearrangement of the extracellular and transmembrane domain ‘wrist’ interface, and leads to rotation of the transmembrane domain toward the pore axis, occluding the ion conduction pathway. These structures illuminate GlyR mechanism and define a rubric to interpret structures of Cys-loop receptors.

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“…9a ). Nevertheless, despite similarly strong interfaces, structural alignments of GABA A R-β3 cryst with other pLGICs reveal differences in their ECD-TMD relative orientations, where rotations within a ~20° range likely reflect the multiplicity of states (resting, activated and desensitised) that these receptors occupy 39 ( Extended Data Fig. 9b-f ).…”

Section: Structural Coupling Between the Extracellular And Transmembrmentioning

confidence: 99%

Crystal structure of a human GABAA receptor

Miller¹,

Aricescu²

2014

Nature

644

678

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SummaryType-A γ-aminobutyric acid receptors (GABAARs) are the principal mediators of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signalling triggers hyperactive neurological disorders such as insomnia, anxiety and epilepsy. Here we present the first three-dimensional structure of a GABAAR, the human β3 homopentamer, at 3 Å resolution. This structure reveals architectural elements unique to eukaryotic Cys-loop receptors, explains the mechanistic consequences of multiple human disease mutations and shows a surprising structural role for a conserved N-linked glycan. The receptor was crystallised bound to a previously unknown agonist, benzamidine, opening a new avenue for the rational design of GABAAR modulators. The channel region forms a closed gate at the base of the pore, representative of a desensitised state. These results offer new insights into the signalling mechanisms of pentameric ligand-gated ion channels and enhance current understanding of GABAergic neurotransmission.

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Using molecular dynamics to elucidate the structural basis for function in pLGICs

Cited by 7 publications

References 23 publications

Agonist and Antagonist Binding in Human Glycine Receptors

Agonist and Antagonist Binding in Human Glycine Receptors

Glycine receptor mechanism elucidated by electron cryo-microscopy

Crystal structure of a human GABAA receptor

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