6xsr

Crystal structure of GluA2 AMPA receptor in complex with trans-4-butylcyclohexane carboxylic acid (4-BCCA) inhibitorCrystal structure of GluA2 AMPA receptor in complex with trans-4-butylcyclohexane carboxylic acid (4-BCCA) inhibitor

Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 4.25Å Ligands: , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed BACKGROUND AND PURPOSE: AMPA receptors, which shape excitatory postsynaptic currents and are directly involved in overactivation of synaptic function during seizures, represent a well-accepted target for anti-epileptic drugs. Trans-4-butylcyclohexane carboxylic acid (4-BCCA) has emerged as a new promising anti-epileptic drug in several in vitro and in vivo seizure models, but the mechanism of its action remained unknown. The purpose of this study is to characterize structure and dynamics of 4-BCCA interaction with AMPA receptors. EXPERIMENTAL APPROACH: We studied the molecular mechanism of AMPA receptor inhibition by 4-BCCA using a combination of X-ray crystallography, mutagenesis, electrophysiological assays, and molecular dynamics simulations. KEY RESULTS: We identified 4-BCCA binding sites in the transmembrane domain (TMD) of AMPA receptor, at the lateral portals formed by transmembrane segments M1-M4. At this binding site, 4-BCCA is very dynamic, assumes multiple poses, and can enter the ion channel pore. CONCLUSION AND IMPLICATIONS: 4-BCCA represents a low-affinity inhibitor of AMPA receptors that acts at the TMD sites distinct from non-competitive inhibitors, such as the anti-epileptic drug perampanel and the ion channel blockers. Further studies might examine the possibsility of synergistic use of these inhibitors in treatment of epilepsy and a wide range of neurological disorders and gliomas. Structural basis of AMPA receptor inhibition by trans-4-butylcyclohexane carboxylic acid.,Yelshanskaya MV, Singh AK, Narangoda C, Williams RSB, Kurnikova MG, Sobolevsky AI Br J Pharmacol. 2020 Sep 22. doi: 10.1111/bph.15254. PMID:32959886 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Glutamate receptor 3D structures

spinqualitylabelsall models 6xsr, resolution 4.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image