This title appears in the Scientific Report :
2020
Please use the identifier:
http://hdl.handle.net/2128/26324 in citations.
Please use the identifier: http://dx.doi.org/10.1126/sciadv.aba9854 in citations.
Na + -dependent gate dynamics and electrostatic attraction ensure substrate coupling in glutamate transporters
Na + -dependent gate dynamics and electrostatic attraction ensure substrate coupling in glutamate transporters
Excitatory amino acid transporters (EAATs) harness [Na+], [K+], and [H+] gradients for fast and efficient glutamate removal from the synaptic cleft. Since each glutamate is cotransported with three Na+ ions, [Na+] gradients are the predominant driving force for glutamate uptake. We combined all-atom...
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Personal Name(s): | Fahlke, Christoph (Corresponding author) |
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Balandin, Taras / Astashkin, Roman / Alleva, Claudia / Machtens, Jan-Philipp (Corresponding author) / Gordeliy, Valentin / Baeken, Christian / Kovalev, Kirill / Berndt, Meike | |
Contributing Institute: |
JARA - HPC; JARA-HPC Strukturbiochemie; IBI-7 Molekular- und Zellphysiologie; IBI-1 |
Published in: | Science advances, 6 (2020) 47, S. eaba9854 - |
Imprint: |
Washington, DC [u.a.]
Assoc.
2020
|
PubMed ID: |
33208356 |
DOI: |
10.1126/sciadv.aba9854 |
Document Type: |
Journal Article |
Research Program: |
Molecular dynamics of the SLC26 family of ion channels and transporters Multiscale simulations of voltage-gated sodium channel complexes and clusters Molecular dynamics simulations of P2X receptors MOLECULAR MODELLING OF BIFUNCTIONAL MEMBRANE TRANSPORT PROTEINS Functional Macromolecules and Complexes |
Link: |
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Publikationsportal JuSER |
Please use the identifier: http://dx.doi.org/10.1126/sciadv.aba9854 in citations.
Excitatory amino acid transporters (EAATs) harness [Na+], [K+], and [H+] gradients for fast and efficient glutamate removal from the synaptic cleft. Since each glutamate is cotransported with three Na+ ions, [Na+] gradients are the predominant driving force for glutamate uptake. We combined all-atom molecular dynamics simulations, fluorescence spectroscopy, and x-ray crystallography to study Na+:substrate coupling in the EAAT homolog GltPh. A lipidic cubic phase x-ray crystal structure of wild-type, Na+-only bound GltPh at 2.5-Å resolution revealed the fully open, outward-facing state primed for subsequent substrate binding. Simulations and kinetic experiments established that only the binding of two Na+ ions to the Na1 and Na3 sites ensures complete HP2 gate opening via a conformational selection-like mechanism and enables high-affinity substrate binding via electrostatic attraction. The combination of Na+-stabilized gate opening and electrostatic coupling of aspartate to Na+ binding provides a constant Na+:substrate transport stoichiometry over a broad range of neurotransmitter concentrations. |