6X01

Crystal structure of the GltPh V216C-A391C mutant cross-linked in outward-facing state

Summary for 6X01

• Entry DOI: 10.2210/pdb6x01/pdb
• Descriptor: Glutamate transporter homolog, ASPARTIC ACID, SODIUM ION (3 entities in total)
• Functional Keywords: glutamate transporter homolog, transport protein
• Biological source: Pyrococcus horikoshii (strain ATCC 700860 / DSM 12428 / JCM 9974 / NBRC 100139 / OT-3)
• Total number of polymer chains: 3
• Total formula weight: 134292.35

Authors

Chen, I.,Font, J.,Ryan, R. (deposition date: 2020-05-15, release date: 2021-02-17, Last modification date: 2024-10-23)

Primary citation

Chen, I.,Pant, S.,Wu, Q.,Cater, R.J.,Sobti, M.,Vandenberg, R.J.,Stewart, A.G.,Tajkhorshid, E.,Font, J.,Ryan, R.M.
Glutamate transporters have a chloride channel with two hydrophobic gates.
Nature, 591:327-331, 2021

PubMed Abstract: Glutamate is the most abundant excitatory neurotransmitter in the central nervous system, and its precise control is vital to maintain normal brain function and to prevent excitotoxicity. The removal of extracellular glutamate is achieved by plasma-membrane-bound transporters, which couple glutamate transport to sodium, potassium and pH gradients using an elevator mechanism. Glutamate transporters also conduct chloride ions by means of a channel-like process that is thermodynamically uncoupled from transport. However, the molecular mechanisms that enable these dual-function transporters to carry out two seemingly contradictory roles are unknown. Here we report the cryo-electron microscopy structure of a glutamate transporter homologue in an open-channel state, which reveals an aqueous cavity that is formed during the glutamate transport cycle. The functional properties of this cavity, combined with molecular dynamics simulations, reveal it to be an aqueous-accessible chloride permeation pathway that is gated by two hydrophobic regions and is conserved across mammalian and archaeal glutamate transporters. Our findings provide insight into the mechanism by which glutamate transporters support their dual function, and add information that will assist in mapping the complete transport cycle shared by the solute carrier 1A transporter family.

PubMed: 33597752
DOI: 10.1038/s41586-021-03240-9

Experimental method

X-RAY DIFFRACTION (3.65 Å)