National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
NS093838
米国
National Institutes of Health/National Cancer Institute (NIH/NCI)
CA206573
米国
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
NS083660
米国
引用
ジャーナル: Neuron / 年: 2018 タイトル: Mechanisms of Channel Block in Calcium-Permeable AMPA Receptors. 著者: Edward C Twomey / Maria V Yelshanskaya / Alexander A Vassilevski / Alexander I Sobolevsky / 要旨: 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 ...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.
超分子 #1: Open state GluA2 in complex with STZ and blocked by NASPM, after ...
超分子
名称: Open state GluA2 in complex with STZ and blocked by NASPM, after micelle signal subtraction タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1 詳細: The full-map (non-TMD-directed) is included as a supplemental file