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Structure paper

タイトル	Structural basis of kainate subtype glutamate receptor desensitization.
ジャーナル・号・ページ	Nature, Vol. 537, Issue 7621, Page 567-571, Year 2016
掲載日	2016年9月22日
著者	Joel R Meyerson / Sagar Chittori / Alan Merk / Prashant Rao / Tae Hee Han / Mihaela Serpe / Mark L Mayer / Sriram Subramaniam /
PubMed 要旨	Glutamate receptors are ligand-gated tetrameric ion channels that mediate synaptic transmission in the central nervous system. They are instrumental in vertebrate cognition and their dysfunction ...Glutamate receptors are ligand-gated tetrameric ion channels that mediate synaptic transmission in the central nervous system. They are instrumental in vertebrate cognition and their dysfunction underlies diverse diseases. In both the resting and desensitized states of AMPA and kainate receptor subtypes, the ion channels are closed, whereas the ligand-binding domains, which are physically coupled to the channels, adopt markedly different conformations. Without an atomic model for the desensitized state, it is not possible to address a central problem in receptor gating: how the resting and desensitized receptor states both display closed ion channels, although they have major differences in the quaternary structure of the ligand-binding domain. Here, by determining the structure of the kainate receptor GluK2 subtype in its desensitized state by cryo-electron microscopy (cryo-EM) at 3.8 Å resolution, we show that desensitization is characterized by the establishment of a ring-like structure in the ligand-binding domain layer of the receptor. Formation of this 'desensitization ring' is mediated by staggered helix contacts between adjacent subunits, which leads to a pseudo-four-fold symmetric arrangement of the ligand-binding domains, illustrating subtle changes in symmetry that are important for the gating mechanism. Disruption of the desensitization ring is probably the key switch that enables restoration of the receptor to its resting state, thereby completing the gating cycle.
リンク	Nature / PubMed:27580033 / PubMed Central
手法	EM (単粒子) / X線回折
解像度	1.271 - 11.6 Å
構造データ	8289 5kuf EMDB-8289, PDB-5kuf: GluK2EM with 2S,4R-4-methylglutamate 手法: EM (単粒子) / 解像度: 3.8 Å 8290 5kuh EMDB-8290, PDB-5kuh: GluK2EM with LY466195 手法: EM (単粒子) / 解像度: 11.6 Å PDB-5cmk: Crystal structure of the GluK2EM LBD dimer assembly complex with glutamate and LY466195 手法: X-RAY DIFFRACTION / 解像度: 1.801 Å PDB-5cmm: Crystal structure of the GluK2EM LBD dimer assembly complex with 2S,4R-4-methylglutamate 手法: X-RAY DIFFRACTION / 解像度: 1.271 Å
化合物	ChemComp-GLU: GLUTAMIC ACID / グルタミン酸 / グルタミン酸 ChemComp-LI: Unknown entry / リチウムカチオン / リチウム ChemComp-CL: Unknown entry / クロリド / 塩化物 ChemComp-LY5: (3S,4aR,6S,8aR)-6-{[(2S)-2-carboxy-4,4-difluoropyrrolidin-1-yl]methyl}decahydroisoquinoline-3-carboxylic acid ChemComp-SO4: SULFATE ION / 硫酸ジアニオン / 硫酸塩 ChemComp-HOH: WATER / 水 ChemComp-SYM: 2S,4R-4-METHYLGLUTAMATE
由来	rattus norvegicus (ドブネズミ) homo sapiens (ヒト)
キーワード	TRANSPORT PROTEIN (運搬体タンパク質) / Membrane protein (膜タンパク質) / SIGNALING PROTEIN / GluK2EM with 2S / 4R-4-methylglutamate / GluK2EM with LY466195