6DLZ

Open state GluA2 in complex with STZ after micelle signal subtraction

Summary for 6DLZ

• Entry DOI: 10.2210/pdb6dlz/pdb
• EMDB information: 7959
• Descriptor: Glutamate receptor 2,Voltage-dependent calcium channel gamma-2 subunit, GLUTAMIC ACID, CYCLOTHIAZIDE (3 entities in total)
• Functional Keywords: ion channel, transport protein
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 4
• Total formula weight: 462862.15

Authors

Twomey, E.C.,Yelshanskaya, M.V.,Vassilevski, A.A.,Sobolevsky, A.I. (deposition date: 2018-06-04, release date: 2018-08-22, Last modification date: 2019-12-18)

Primary citation

Twomey, E.C.,Yelshanskaya, M.V.,Vassilevski, A.A.,Sobolevsky, A.I.
Mechanisms of Channel Block in Calcium-Permeable AMPA Receptors.
Neuron, 99:956-968.e4, 2018

PubMed Abstract: AMPA receptors mediate fast excitatory neurotransmission and are critical for CNS development and function. Calcium-permeable subsets of AMPA receptors are strongly implicated in acute and chronic neurological disorders. However, despite the clinical importance, the therapeutic landscape for specifically targeting them, and not the calcium-impermeable AMPA receptors, remains largely undeveloped. To address this problem, we used cryo-electron microscopy and electrophysiology to investigate the mechanisms by which small-molecule blockers selectively inhibit ion channel conductance in calcium-permeable AMPA receptors. We determined the structures of calcium-permeable GluA2 AMPA receptor complexes with the auxiliary subunit stargazin bound to channel blockers, including the orb weaver spider toxin AgTx-636, the spider toxin analog NASPM, and the adamantane derivative IEM-1460. Our structures provide insights into the architecture of the blocker binding site and the mechanism of trapping, which are critical for development of small molecules that specifically target calcium-permeable AMPA receptors.

PubMed: 30122377
DOI: 10.1016/j.neuron.2018.07.027

Experimental method

ELECTRON MICROSCOPY (3.9 Å)