+データを開く
-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 | ||||||||||||
要素 |
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キーワード | MEMBRANE PROTEIN / GPCR / Cannabinoid receptor 1 / THC analog complex | ||||||||||||
機能・相同性 | 機能・相同性情報 cannabinoid signaling pathway / regulation of penile erection / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / negative regulation of mast cell activation / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / negative regulation of fatty acid beta-oxidation / regulation of feeding behavior / negative regulation of dopamine secretion / positive regulation of acute inflammatory response to antigenic stimulus ...cannabinoid signaling pathway / regulation of penile erection / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / negative regulation of mast cell activation / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / negative regulation of fatty acid beta-oxidation / regulation of feeding behavior / negative regulation of dopamine secretion / positive regulation of acute inflammatory response to antigenic stimulus / negative regulation of serotonin secretion / regulation of presynaptic cytosolic calcium ion concentration / negative regulation of action potential / Class A/1 (Rhodopsin-like receptors) / positive regulation of blood pressure / positive regulation of fever generation / regulation of metabolic process / axonal fasciculation / regulation of synaptic transmission, GABAergic / regulation of insulin secretion / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / T cell migration / D2 dopamine receptor binding / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / maternal process involved in female pregnancy / regulation of cAMP-mediated signaling / G protein-coupled serotonin receptor binding / cellular response to forskolin / GABA-ergic synapse / regulation of mitotic spindle organization / regulation of synaptic transmission, glutamatergic / negative regulation of blood pressure / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / response to nutrient / response to cocaine / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / response to nicotine / adenylate cyclase-activating G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / 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 / G beta:gamma signalling through CDC42 / memory / positive regulation of neuron projection development / response to peptide hormone / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GDP binding / cellular response to prostaglandin E stimulus / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / actin cytoskeleton / signaling receptor complex adaptor activity / 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 / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / glucose homeostasis / retina development in camera-type eye / presynaptic membrane / Ca2+ pathway / cell cortex / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / midbody / growth cone / fibroblast proliferation / spermatogenesis / G alpha (s) signalling events 類似検索 - 分子機能 | ||||||||||||
生物種 | Homo sapiens (ヒト) Mus musculus (ハツカネズミ) | ||||||||||||
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 | ||||||||||||
データ登録者 | Thorsen, T.S. / Kulkarni, Y. / Boggild, A. / Drace, T. / Nissen, P. / Gajhede, M. / Boesen, T. / Kastrup, J.S. / Gloriam, D. | ||||||||||||
資金援助 | デンマーク, 3件
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引用 | ジャーナル: Res Sq / 年: 2024 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: MolmilJmol/JSmol |
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-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 9erx.cif.gz | 224.9 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb9erx.ent.gz | 表示 | PDB形式 | |
PDBx/mmJSON形式 | 9erx.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
その他 | その他のダウンロード |
-検証レポート
文書・要旨 | 9erx_validation.pdf.gz | 1.2 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 9erx_full_validation.pdf.gz | 1.2 MB | 表示 | |
XML形式データ | 9erx_validation.xml.gz | 43 KB | 表示 | |
CIF形式データ | 9erx_validation.cif.gz | 65.7 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/er/9erx ftp://data.pdbj.org/pub/pdb/validation_reports/er/9erx | 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 (文献) |
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類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-リンク
-集合体
登録構造単位 |
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1 |
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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) Homo sapiens (ヒト) / 遺伝子: GNAI1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 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) Homo sapiens (ヒト) / 遺伝子: GNB1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 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) Homo sapiens (ヒト) / 遺伝子: GNG2 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 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) Homo sapiens (ヒト) / 遺伝子: CNR1, CNR 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 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) Mus musculus (ハツカネズミ) / 発現宿主: Trichoplusia ni (イラクサキンウワバ) |
-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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-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 |
-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 |
-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: FIELD EMISSION GUN / 加速電圧: 300 kV / 照射モード: FLOOD BEAM |
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 |
-解析
EMソフトウェア | 名称: EPU / バージョン: 2.7 / カテゴリ: 画像取得 | ||||||||||||||||||||||||
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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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