scholarly journals On the functional annotation of open-channel structures in the glycine receptor

2020 ◽  
Author(s):  
Adrien Henri Cerdan ◽  
Marco Cecchini
Keyword(s):  
Open Channel ◽  
Lipid Membrane ◽  
Glycine Receptor ◽  
Active State ◽  
Pore Geometry ◽  
X Ray ◽  
X Ray Crystallography ◽  
Computational Electrophysiology ◽  
Dynamics Simulations ◽  
Channel Structures

AbstractThe glycine receptor (GlyR) is by far the best-characterized pentameric ligand-gated ion channel with several high-resolution structures from X-ray crystallography, cryo-EM and modeling. Nonetheless, the significance of the currently available open-pore conformations is debated due to their diversity in the pore geometry. Here, we discuss the physiological significance of existing models of the GlyR active state based on conductance and selectivity measurements by computational electrophysiology. The results support the conclusion that the original cryo-EM reconstruction of the active state obtained in detergents as well as its subsequent refinement by Molecular Dynamics simulations are likely to be non-physiological as they feature artificially dilated ion pores. In addition, the calculations indicate that a physiologically relevant open pore configuration should be constricted within a radius of 2.5 and 2.8Å, which is consistent with previous modeling, electrophysiology measurements, and the most recent cryo-EM structures obtained in a native lipid-membrane environment.

scholarly journals Comment on “On the Functional Annotation of Open-Channel Structures in the Glycine Receptor”

Structure ◽  
2020 ◽  
Vol 28 (6) ◽  
pp. 601-603
Author(s):  
Marc A. Dämgen ◽  
Afroditi Maria Zaki ◽  
Philip C. Biggin
Keyword(s):  
Functional Annotation ◽  
Open Channel ◽  
Glycine Receptor ◽  
Channel Structures

scholarly journals Elucidation of Lipid Binding Sites on Lung Surfactant Protein A Using X-ray Crystallography, Mutagenesis, and Molecular Dynamics Simulations

Biochemistry ◽  
2016 ◽  
Vol 55 (26) ◽  
pp. 3692-3701 ◽  
Author(s):  
Boon Chong Goh ◽  
Huixing Wu ◽  
Michael J. Rynkiewicz ◽  
Klaus Schulten ◽  
Barbara A. Seaton ◽  
...  
Keyword(s):  
Binding Sites ◽  
Lung Surfactant ◽  
Protein A ◽  
Surfactant Protein ◽  
Lipid Binding ◽  
Surfactant Protein A ◽  
X Ray ◽  
X Ray Crystallography ◽  
Lung Surfactant Protein ◽  
Dynamics Simulations

scholarly journals Mixed Chirality α-Helix in a Stapled Bicyclic and a Linear Antimicrobial Peptide Revealed by X-Ray Crystallography

2021 ◽  
Author(s):  
stéphane Baeriswyl ◽  
Hippolyte Personne ◽  
Ivan Di Bonaventura ◽  
Thilo Köhler ◽  
Christian van Delden ◽  
...  
Keyword(s):  
Bioactive Peptides ◽  
Multidrug Resistant ◽  
Isobutyric Acid ◽  
Resistant Bacteria ◽  
X Ray ◽  
X Ray Crystallography ◽  
Left Handed ◽  
Amino Isobutyric Acid ◽  
Α Helix ◽  
Dynamics Simulations

<p>The peptide α-helix is right-handed when containing amino acids with L-chirality, and left-handed with D-chirality. What happens in between is largely unknown, however α-helices have not been reported with mixed chirality sequences unless a strong non-natural helix inducer such as amino-isobutyric acid was used. Herein we report the discovery of a membrane disruptive amphiphilic antimicrobial undecapeptide containing seven L- and four D-residues forming a stable right-handed α-helix in stapled bicyclic and linear forms. The α-helical fold is evidenced by X-ray crystallography and supported in solution by circular dichroism spectra as well as molecular dynamics simulations. The linear mixed chirality peptide is as active as the L-sequence against multidrug resistant bacteria but shows no hemolysis and full stability against serum proteolysis. Searching for mixed chirality analogs preserving folding might be generally useful to optimize α-helical bioactive peptides. </p>

scholarly journals Mixed Chirality α-Helix in a Stapled Bicyclic and a Linear Antimicrobial Peptide Revealed by X-Ray Crystallography

2021 ◽  
Author(s):  
stéphane Baeriswyl ◽  
Hippolyte Personne ◽  
Ivan Di Bonaventura ◽  
Thilo Köhler ◽  
Christian van Delden ◽  
...  
Keyword(s):  
Bioactive Peptides ◽  
Multidrug Resistant ◽  
Isobutyric Acid ◽  
Resistant Bacteria ◽  
X Ray ◽  
X Ray Crystallography ◽  
Left Handed ◽  
Amino Isobutyric Acid ◽  
Α Helix ◽  
Dynamics Simulations

<p>The peptide α-helix is right-handed when containing amino acids with L-chirality, and left-handed with D-chirality. What happens in between is largely unknown, however α-helices have not been reported with mixed chirality sequences unless a strong non-natural helix inducer such as amino-isobutyric acid was used. Herein we report the discovery of a membrane disruptive amphiphilic antimicrobial undecapeptide containing seven L- and four D-residues forming a stable right-handed α-helix in stapled bicyclic and linear forms. The α-helical fold is evidenced by X-ray crystallography and supported in solution by circular dichroism spectra as well as molecular dynamics simulations. The linear mixed chirality peptide is as active as the L-sequence against multidrug resistant bacteria but shows no hemolysis and full stability against serum proteolysis. Searching for mixed chirality analogs preserving folding might be generally useful to optimize α-helical bioactive peptides. </p>

scholarly journals A pharmacological master key mechanism that unlocks the selectivity filter gate in K+channels

Science ◽  
2019 ◽  
Vol 363 (6429) ◽  
pp. 875-880 ◽  
Author(s):  
Marcus Schewe ◽  
Han Sun ◽  
Ümit Mert ◽  
Alexandra Mackenzie ◽  
Ashley C. W. Pike ◽  
...  
Keyword(s):  
Selectivity Filter ◽  
Rational Drug Design ◽  
Related Gene ◽  
K Channels ◽  
X Ray ◽  
Voltage Gated ◽  
X Ray Crystallography ◽  
Rational Drug ◽  
Dynamics Simulations ◽  
Pore Domain

Potassium (K+) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) that bypass the specific mechanisms but act as master keys to open K+channels gated at their selectivity filter (SF), including many two-pore domain K+(K2P) channels, voltage-gated hERG (human ether-à-go-go–related gene) channels and calcium (Ca2+)–activated big-conductance potassium (BK)–type channels. Functional analysis, x-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the SF, increase pore and SF K+occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K+channel activators and highlight a filter gating machinery that is conserved across different families of K+channels with implications for rational drug design.

scholarly journals Backdoor opening mechanism in acetylcholinesterase based on X-ray crystallography and molecular dynamics simulations

2011 ◽  
Vol 20 (7) ◽  
pp. 1114-1118 ◽  
Author(s):  
Benoît Sanson ◽  
Jacques-Philippe Colletier ◽  
Yechun Xu ◽  
P. Therese Lang ◽  
Hualiang Jiang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
X Ray ◽  
X Ray Crystallography ◽  
Dynamics Simulations
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