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PDBsum entry 6hya
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Membrane protein
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PDB id
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6hya
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References listed in PDB file
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Key reference
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Title
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Electrostatics, Proton sensor, And networks governing the gating transition in glic, A proton-Gated pentameric ion channel.
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Authors
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H.Hu,
K.Ataka,
A.Menny,
Z.Fourati,
L.Sauguet,
P.J.Corringer,
P.Koehl,
J.Heberle,
M.Delarue.
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Ref.
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Proc Natl Acad Sci U S A, 2018,
115,
E12172.
[DOI no: ]
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PubMed id
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Abstract
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The pentameric ligand-gated ion channel (pLGIC) from Gloeobacter
violaceus (GLIC) has provided insightful structure-function views on the
permeation process and the allosteric regulation of the pLGICs family. However,
GLIC is activated by pH instead of a neurotransmitter and a clear picture for
the gating transition driven by protons is still lacking. We used an
electrostatics-based (finite difference Poisson-Boltzmann/Debye-Hückel) method
to predict the acidities of all aspartic and glutamic residues in GLIC, both in
its active and closed-channel states. Those residues with a predicted
pKa close to the experimental pH50 were individually
replaced by alanine and the resulting variant receptors were titrated by
ATR/FTIR spectroscopy. E35, located in front of loop F far away from the
orthosteric site, appears as the key proton sensor with a measured individual
pKa at 5.8. In the GLIC open conformation, E35 is connected through a
water-mediated hydrogen-bond network first to the highly conserved electrostatic
triad R192-D122-D32 and then to Y197-Y119-K248, both located at the
extracellular domain-transmembrane domain interface. The second triad controls a
cluster of hydrophobic side chains from the M2-M3 loop that is remodeled during
the gating transition. We solved 12 crystal structures of GLIC mutants, 6 of
them being trapped in an agonist-bound but nonconductive conformation. Combined
with previous data, this reveals two branches of a continuous network
originating from E35 that reach, independently, the middle transmembrane region
of two adjacent subunits. We conclude that GLIC's gating proceeds by making use
of loop F, already known as an allosteric site in other pLGICs, instead of the
classic orthosteric site.
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