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基本情報
登録情報 | データベース: PDB / ID: 9erx | |||||||||||||||||||||||||||||||||||||||||||||
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タイトル | Structural basis of D9-THC analog activity at the Cannabinoid 1 receptor | |||||||||||||||||||||||||||||||||||||||||||||
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![]() | MEMBRANE PROTEIN / GPCR / Cannabinoid receptor 1 / THC analog complex | |||||||||||||||||||||||||||||||||||||||||||||
機能・相同性 | ![]() cannabinoid signaling pathway / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / regulation of presynaptic cytosolic calcium ion concentration / Class A/1 (Rhodopsin-like receptors) / axonal fasciculation / regulation of metabolic process / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex ...cannabinoid signaling pathway / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / regulation of presynaptic cytosolic calcium ion concentration / Class A/1 (Rhodopsin-like receptors) / axonal fasciculation / regulation of metabolic process / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / response to prostaglandin E / adenylate cyclase regulator activity / G protein-coupled serotonin receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / cellular response to forskolin / regulation of mitotic spindle organization / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / G protein-coupled receptor activity / G protein-coupled receptor binding / response to peptide hormone / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / GABA-ergic synapse / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / centriolar satellite / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / GDP binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / glucose homeostasis / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / actin cytoskeleton / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / G protein activity / growth cone / presynaptic membrane / GTPase binding / Ca2+ pathway / midbody / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / cell cortex / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / 加水分解酵素; 酸無水物に作用; GTPに作用・細胞または細胞小器官の運動に関与 / mitochondrial outer membrane / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / ciliary basal body / G protein-coupled receptor signaling pathway / membrane raft / lysosomal membrane / cell division / GTPase activity / synapse / centrosome / GTP binding 類似検索 - 分子機能 | |||||||||||||||||||||||||||||||||||||||||||||
生物種 | ![]() ![]() ![]() | |||||||||||||||||||||||||||||||||||||||||||||
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: 2.9 Å | |||||||||||||||||||||||||||||||||||||||||||||
![]() | Thorsen, T.S. / Kulkarni, Y. / Boggild, A. / Drace, T. / Nissen, P. / Gajhede, M. / Boesen, T. / Kastrup, J.S. / Gloriam, D. | |||||||||||||||||||||||||||||||||||||||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structural basis of Δ-THC analog activity at the Cannabinoid 1 receptor. 著者: David Gloriam / Thor Thorsen / Yashraj Kulkarni / David Sykes / Andreas Bøggild / Taner Drace / Pattarin Hompluem / Christos Iliopoulos-Tsoutsouvas / Spyros Nikas / Henrik Daver / Alexandros ...著者: David Gloriam / Thor Thorsen / Yashraj Kulkarni / David Sykes / Andreas Bøggild / Taner Drace / Pattarin Hompluem / Christos Iliopoulos-Tsoutsouvas / Spyros Nikas / Henrik Daver / Alexandros Makriyannis / Poul Nissen / Michael Gajhede / Dmitry Veprintsev / Thomas Boesen / Jette Kastrup 要旨: Δ-tetrahydrocannabinol (THC) is the principal psychoactive compound derived from the cannabis plant Cannabis sativa and approved for emetic conditions, appetite stimulation and sleep apnea relief. ...Δ-tetrahydrocannabinol (THC) is the principal psychoactive compound derived from the cannabis plant Cannabis sativa and approved for emetic conditions, appetite stimulation and sleep apnea relief. THC's psychoactive actions are mediated primarily by the cannabinoid receptor CB. Here, we determine the cryo-EM structure of HU210, a THC analog and widely used tool compound, bound to CB and its primary transducer, G. We leverage this structure for docking and 1,000 ns molecular dynamics simulations of THC and 10 structural analogs delineating their spatiotemporal interactions at the molecular level. Furthermore, we pharmacologically profile their recruitment of G and β-arrestins and reversibility of binding from an active complex. By combining detailed CB structural information with molecular models and signaling data we uncover the differential spatiotemporal interactions these ligands make to receptors governing potency, efficacy, bias and kinetics. This may help explain the actions of abused substances, advance fundamental receptor activation studies and design better medicines. | |||||||||||||||||||||||||||||||||||||||||||||
履歴 |
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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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ダウンロード
PDBx/mmCIF形式 | ![]() | 225.5 KB | 表示 | ![]() |
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PDB形式 | ![]() | 表示 | ![]() | |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
文書・要旨 | ![]() | 1.2 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.2 MB | 表示 | |
XML形式データ | ![]() | 42.4 KB | 表示 | |
CIF形式データ | ![]() | 66.2 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 | ![]() 19929MC 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 ABC
#1: タンパク質 | 分子量: 40313.863 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: P63096 |
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#2: タンパク質 | 分子量: 39418.086 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: P62873 |
#3: タンパク質 | 分子量: 7861.143 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: P59768 |
-タンパク質 / 抗体 , 2種, 2分子 RF
#4: タンパク質 | 分子量: 57122.426 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: P21554 |
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#5: 抗体 | 分子量: 32898.781 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() |
-非ポリマー , 2種, 2分子 
#6: 化合物 | ChemComp-A1H66 / ( 分子量: 386.567 Da / 分子数: 1 / 由来タイプ: 合成 / 式: C25H38O3 / タイプ: SUBJECT OF INVESTIGATION |
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#7: 水 | ChemComp-HOH / |
-詳細
研究の焦点であるリガンドがあるか | Y |
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Has protein modification | Y |
-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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由来(天然) |
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由来(組換発現) |
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緩衝液 | pH: 7.4 | ||||||||||||||||||||||||
試料 | 濃度: 0.85 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES | ||||||||||||||||||||||||
試料支持 | グリッドの材料: GOLD / グリッドのサイズ: 300 divisions/in. / グリッドのタイプ: Quantifoil | ||||||||||||||||||||||||
急速凍結 | 装置: LEICA EM GP / 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 / 最大 デフォーカス(公称値): 1800 nm / 最小 デフォーカス(公称値): 600 nm / Cs: 2.7 mm / C2レンズ絞り径: 50 µm |
撮影 | 平均露光時間: 1.5 sec. / 電子線照射量: 60.6 e/Å2 フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) |
電子光学装置 | エネルギーフィルター名称: GIF Bioquantum / エネルギーフィルタースリット幅: 20 eV |
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解析
EMソフトウェア |
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3次元再構成 | 解像度: 2.9 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 187493 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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