4Z90

ELIC bound with the anesthetic isoflurane in the resting state

Summary for 4Z90

• Entry DOI: 10.2210/pdb4z90/pdb
• Related: 3RQU 3RQW
• Descriptor: Gamma-aminobutyric-acid receptor subunit beta-1, (2R)-2-chloro-2-(difluoromethoxy)-1,1,1-trifluoroethane, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (4 entities in total)
• Functional Keywords: elic, isoflurane, inhibition, anesthetics, resting state, transport protein
• Biological source: Dickeya dadantii (strain 3937)
• Total number of polymer chains: 10
• Total formula weight: 371480.34

Authors

Chen, Q.,Kinde, M.,Arjunan, P.,Cohen, A.,Xu, Y.,Tang, P. (deposition date: 2015-04-09, release date: 2015-09-16, Last modification date: 2023-09-27)

Primary citation

Chen, Q.,Kinde, M.N.,Arjunan, P.,Wells, M.M.,Cohen, A.E.,Xu, Y.,Tang, P.
Direct Pore Binding as a Mechanism for Isoflurane Inhibition of the Pentameric Ligand-gated Ion Channel ELIC.
Sci Rep, 5:13833-13833, 2015

PubMed Abstract: Pentameric ligand-gated ion channels (pLGICs) are targets of general anesthetics, but molecular mechanisms underlying anesthetic action remain debatable. We found that ELIC, a pLGIC from Erwinia chrysanthemi, can be functionally inhibited by isoflurane and other anesthetics. Structures of ELIC co-crystallized with isoflurane in the absence or presence of an agonist revealed double isoflurane occupancies inside the pore near T237(6') and A244(13'). A pore-radius contraction near the extracellular entrance was observed upon isoflurane binding. Electrophysiology measurements with a single-point mutation at position 6' or 13' support the notion that binding at these sites renders isoflurane inhibition. Molecular dynamics simulations suggested that isoflurane binding was more stable in the resting than in a desensitized pore conformation. This study presents compelling evidence for a direct pore-binding mechanism of isoflurane inhibition, which has a general implication for inhibitory action of general anesthetics on pLGICs.

PubMed: 26346220
DOI: 10.1038/srep13833

Experimental method

X-RAY DIFFRACTION (3 Å)