4IRE

Crystal structure of GLIC with mutations at the loop C region

Summary for 4IRE

• Entry DOI: 10.2210/pdb4ire/pdb
• Descriptor: Proton-gated ion channel, tetradecyl 4-O-alpha-D-glucopyranosyl-beta-D-glucopyranoside, 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE, ... (6 entities in total)
• Functional Keywords: transport protein, pentameric ligand-gated ion channel, proton-gated ion channel
• Biological source: Gloeobacter violaceus
• Cellular location: Cell inner membrane; Multi-pass membrane protein (Probable): Q7NDN8
• Total number of polymer chains: 5
• Total formula weight: 194594.06

Authors

Chen, Q.,Pan, J.,Liang, Y.H.,Xu, Y.,Tang, P. (deposition date: 2013-01-14, release date: 2013-04-24, Last modification date: 2023-09-20)

Primary citation

Mowrey, D.,Chen, Q.,Liang, Y.,Liang, J.,Xu, Y.,Tang, P.
Signal transduction pathways in the pentameric ligand-gated ion channels.
Plos One, 8:e64326-e64326, 2013

PubMed Abstract: The mechanisms of allosteric action within pentameric ligand-gated ion channels (pLGICs) remain to be determined. Using crystallography, site-directed mutagenesis, and two-electrode voltage clamp measurements, we identified two functionally relevant sites in the extracellular (EC) domain of the bacterial pLGIC from Gloeobacter violaceus (GLIC). One site is at the C-loop region, where the NQN mutation (D91N, E177Q, and D178N) eliminated inter-subunit salt bridges in the open-channel GLIC structure and thereby shifted the channel activation to a higher agonist concentration. The other site is below the C-loop, where binding of the anesthetic ketamine inhibited GLIC currents in a concentration dependent manner. To understand how a perturbation signal in the EC domain, either resulting from the NQN mutation or ketamine binding, is transduced to the channel gate, we have used the Perturbation-based Markovian Transmission (PMT) model to determine dynamic responses of the GLIC channel and signaling pathways upon initial perturbations in the EC domain of GLIC. Despite the existence of many possible routes for the initial perturbation signal to reach the channel gate, the PMT model in combination with Yen's algorithm revealed that perturbation signals with the highest probability flow travel either via the β1-β2 loop or through pre-TM1. The β1-β2 loop occurs in either intra- or inter-subunit pathways, while pre-TM1 occurs exclusively in inter-subunit pathways. Residues involved in both types of pathways are well supported by previous experimental data on nAChR. The direct coupling between pre-TM1 and TM2 of the adjacent subunit adds new insight into the allosteric signaling mechanism in pLGICs.

PubMed: 23667707
DOI: 10.1371/journal.pone.0064326

Experimental method

X-RAY DIFFRACTION (3.19 Å)