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基本情報
登録情報 | データベース: PDB / ID: 7sqo | ||||||
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タイトル | Structure of the orexin-2 receptor(OX2R) bound to TAK-925, Gi and scFv16 | ||||||
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![]() | MEMBRANE PROTEIN / CLASS A GPCR | ||||||
機能・相同性 | ![]() regulation of circadian sleep/wake cycle, wakefulness / circadian sleep/wake cycle process / orexin receptor activity / Orexin and neuropeptides FF and QRFP bind to their respective receptors / neuropeptide receptor activity / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Activation of the phototransduction cascade / feeding behavior ...regulation of circadian sleep/wake cycle, wakefulness / circadian sleep/wake cycle process / orexin receptor activity / Orexin and neuropeptides FF and QRFP bind to their respective receptors / neuropeptide receptor activity / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Activation of the phototransduction cascade / feeding behavior / locomotion / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / G alpha (q) signalling events / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / peptide hormone binding / Adenylate cyclase inhibitory pathway / neuropeptide signaling pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / cellular response to hormone stimulus / regulation of cytosolic calcium ion concentration / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Regulation of insulin secretion / G protein-coupled receptor binding / peptide binding / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / ADP signalling through P2Y purinoceptor 12 / response to peptide hormone / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / GPER1 signaling / GDP binding / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / phospholipase C-activating G protein-coupled receptor signaling pathway / cell cortex / midbody / G alpha (i) signalling events / G alpha (s) signalling events / G alpha (q) signalling events / chemical synaptic transmission / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / cell cycle / cell division / lysosomal membrane / GTPase activity / centrosome / synapse / nucleolus / GTP binding / magnesium ion binding / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytoplasm 類似検索 - 分子機能 | ||||||
生物種 | ![]() ![]() ![]() synthetic construct (人工物) | ||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.17 Å | ||||||
![]() | McGrath, A.P. / Kang, Y. / Flinspach, M. | ||||||
資金援助 | 1件
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![]() | ![]() タイトル: Molecular mechanism of the wake-promoting agent TAK-925. 著者: Jie Yin / Yanyong Kang / Aaron P McGrath / Karen Chapman / Megan Sjodt / Eiji Kimura / Atsutoshi Okabe / Tatsuki Koike / Yuhei Miyanohana / Yuji Shimizu / Rameshu Rallabandi / Peng Lian / ...著者: Jie Yin / Yanyong Kang / Aaron P McGrath / Karen Chapman / Megan Sjodt / Eiji Kimura / Atsutoshi Okabe / Tatsuki Koike / Yuhei Miyanohana / Yuji Shimizu / Rameshu Rallabandi / Peng Lian / Xiaochen Bai / Mack Flinspach / Jef K De Brabander / Daniel M Rosenbaum / ![]() ![]() ![]() 要旨: The OX orexin receptor (OXR) is a highly expressed G protein-coupled receptor (GPCR) in the brain that regulates wakefulness and circadian rhythms in humans. Antagonism of OXR is a proven therapeutic ...The OX orexin receptor (OXR) is a highly expressed G protein-coupled receptor (GPCR) in the brain that regulates wakefulness and circadian rhythms in humans. Antagonism of OXR is a proven therapeutic strategy for insomnia drugs, and agonism of OXR is a potentially powerful approach for narcolepsy type 1, which is characterized by the death of orexinergic neurons. Until recently, agonism of OXR had been considered 'undruggable.' We harness cryo-electron microscopy of OXR-G protein complexes to determine how the first clinically tested OXR agonist TAK-925 can activate OXR in a highly selective manner. Two structures of TAK-925-bound OXR with either a G mimetic or G reveal that TAK-925 binds at the same site occupied by antagonists, yet interacts with the transmembrane helices to trigger activating microswitches. Our structural and mutagenesis data show that TAK-925's selectivity is mediated by subtle differences between OX and OX receptor subtypes at the orthosteric pocket. Finally, differences in the polarity of interactions at the G protein binding interfaces help to rationalize OXR's coupling selectivity for G signaling. The mechanisms of TAK-925's binding, activation, and selectivity presented herein will aid in understanding the efficacy of small molecule OXR agonists for narcolepsy and other circadian disorders. | ||||||
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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ダウンロードとリンク
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PDBx/mmCIF形式 | ![]() | 373.4 KB | 表示 | ![]() |
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PDB形式 | ![]() | 300 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
文書・要旨 | ![]() | 971.2 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 985.2 KB | 表示 | |
XML形式データ | ![]() | 40.8 KB | 表示 | |
CIF形式データ | ![]() | 61.8 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 25389MC ![]() 7sr8C M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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リンク
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集合体
登録構造単位 | ![]()
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要素
-Guanine nucleotide-binding protein ... , 3種, 3分子 ABG
#2: タンパク質 | 分子量: 40459.039 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
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#3: タンパク質 | 分子量: 39151.855 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() |
#4: タンパク質 | 分子量: 7563.750 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() |
-タンパク質 / 抗体 , 2種, 2分子 RE
#1: タンパク質 | 分子量: 50733.289 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
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#5: 抗体 | 分子量: 26277.299 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) synthetic construct (人工物) / 発現宿主: ![]() |
-非ポリマー , 2種, 5分子 ![](data/chem/img/OLA.gif)
![](data/chem/img/A6F.gif)
![](data/chem/img/A6F.gif)
#6: 化合物 | ChemComp-OLA / #7: 化合物 | ChemComp-A6F / | |
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-詳細
研究の焦点であるリガンドがあるか | Y |
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-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
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試料調製
構成要素 |
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分子量 | 実験値: NO | ||||||||||||||||||||||||||||||||||||
由来(天然) |
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由来(組換発現) |
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緩衝液 | pH: 7.2 | ||||||||||||||||||||||||||||||||||||
試料 | 濃度: 5 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES | ||||||||||||||||||||||||||||||||||||
急速凍結 | 凍結剤: ETHANE |
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電子顕微鏡撮影
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TITAN KRIOS |
電子銃 | 電子線源: ![]() |
電子レンズ | モード: BRIGHT FIELD / 倍率(公称値): 130000 X / Cs: 2.7 mm |
撮影 | 電子線照射量: 43.7 e/Å2 フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) 詳細: Cryo-EM movie stacks were collected on a Titan Krios microscope operated at 300 kV under EFTEM mode. Nanoprobe with 1um illumination area was used. Data were recorded on a postGIF Gatan K2 ...詳細: Cryo-EM movie stacks were collected on a Titan Krios microscope operated at 300 kV under EFTEM mode. Nanoprobe with 1um illumination area was used. Data were recorded on a postGIF Gatan K2 summit camera at a nominal magnification of 130,000, using super-resolution counting model. Bioquantum energy filter was operated in the zero-energy-loss mode with an energy slit width of 20 eV. |
電子光学装置 | エネルギーフィルター名称: GIF Bioquantum |
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解析
ソフトウェア |
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EMソフトウェア |
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画像処理 | 詳細: Frames 2-30 were used during dose-weighted movie frame alignment to reduce effects of beam-induced motion. Parameters of the FEI Titan Krios contrast transfer function were subsequently ...詳細: Frames 2-30 were used during dose-weighted movie frame alignment to reduce effects of beam-induced motion. Parameters of the FEI Titan Krios contrast transfer function were subsequently estimated for each micrograph. A total 647,261 particles were auto-picked using Template Picker and extracted in 220 x 220 pixels box using cryoSPARC. All particles were subject to three rounds of reference-free 2D classification. Four initial model were made using cryoSPARC based on selected particles. The final 3D refinement in cryoSPARC2 used 251,169 particles, producing a reconstruction with 3.17A nominal resolution. | ||||||||||||||||||||||||
CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
粒子像の選択 | 選択した粒子像数: 647261 | ||||||||||||||||||||||||
3次元再構成 | 解像度: 3.17 Å / 解像度の算出法: FSC 0.5 CUT-OFF / 粒子像の数: 251169 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
原子モデル構築 | プロトコル: RIGID BODY FIT | ||||||||||||||||||||||||
精密化 | 交差検証法: NONE 立体化学のターゲット値: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
原子変位パラメータ | Biso mean: 107.86 Å2 | ||||||||||||||||||||||||
拘束条件 |
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