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基本情報
登録情報 | データベース: EMDB / ID: EMD-23280 | |||||||||
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タイトル | Cryo-EM structure of the human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist and an allosteric ligand | |||||||||
![]() | Final masked map | |||||||||
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![]() | signaling protein / membrane protein / active-state G protein-coupled receptor / adenosine A1 receptor / PAM / allosteric modulator | |||||||||
機能・相同性 | ![]() positive regulation of nucleoside transport / negative regulation of neurotrophin production / negative regulation of circadian sleep/wake cycle, non-REM sleep / regulation of glomerular filtration / purine nucleoside binding / positive regulation of peptide secretion / negative regulation of mucus secretion / negative regulation of glutamate secretion / negative regulation of long-term synaptic depression / Muscarinic acetylcholine receptors ...positive regulation of nucleoside transport / negative regulation of neurotrophin production / negative regulation of circadian sleep/wake cycle, non-REM sleep / regulation of glomerular filtration / purine nucleoside binding / positive regulation of peptide secretion / negative regulation of mucus secretion / negative regulation of glutamate secretion / negative regulation of long-term synaptic depression / Muscarinic acetylcholine receptors / G protein-coupled acetylcholine receptor activity / positive regulation of lipid catabolic process / negative regulation of synaptic transmission, GABAergic / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / negative regulation of hormone secretion / negative regulation of leukocyte migration / mucus secretion / heterotrimeric G-protein binding / positive regulation of dephosphorylation / Adenosine P1 receptors / G protein-coupled adenosine receptor activity / regulation of sensory perception of pain / regulation of respiratory gaseous exchange by nervous system process / regulation of presynaptic cytosolic calcium ion concentration / negative regulation of calcium ion-dependent exocytosis / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / response to purine-containing compound / G protein-coupled adenosine receptor signaling pathway / negative regulation of adenylate cyclase activity / positive regulation of urine volume / positive regulation of potassium ion transport / positive regulation of neural precursor cell proliferation / negative regulation of synaptic transmission / negative regulation of synaptic transmission, glutamatergic / negative regulation of systemic arterial blood pressure / regulation of cardiac muscle cell contraction / triglyceride homeostasis / protein targeting to membrane / long-term synaptic depression / leukocyte migration / regulation of locomotion / gamma-aminobutyric acid signaling pathway / temperature homeostasis / neuronal dense core vesicle / positive regulation of systemic arterial blood pressure / negative regulation of acute inflammatory response / detection of temperature stimulus involved in sensory perception of pain / presynaptic active zone / negative regulation of apoptotic signaling pathway / regulation of calcium ion transport / negative regulation of long-term synaptic potentiation / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / asymmetric synapse / axolemma / phagocytosis / fatty acid homeostasis / negative regulation of lipid catabolic process / Adenylate cyclase inhibitory pathway / lipid catabolic process / positive regulation of vascular associated smooth muscle cell proliferation / heat shock protein binding / response to nutrient / calyx of Held / hippocampal mossy fiber to CA3 synapse / positive regulation of superoxide anion generation / excitatory postsynaptic potential / Regulation of insulin secretion / apoptotic signaling pathway / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / terminal bouton / G-protein beta/gamma-subunit complex binding / cognition / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / 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 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / vasodilation / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 類似検索 - 分子機能 | |||||||||
生物種 | ![]() | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.2 Å | |||||||||
![]() | Draper-Joyce CJ / Danev R | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Positive allosteric mechanisms of adenosine A receptor-mediated analgesia. 著者: Christopher J Draper-Joyce / Rebecca Bhola / Jinan Wang / Apurba Bhattarai / Anh T N Nguyen / India Cowie-Kent / Kelly O'Sullivan / Ling Yeong Chia / Hariprasad Venugopal / Celine Valant / ...著者: Christopher J Draper-Joyce / Rebecca Bhola / Jinan Wang / Apurba Bhattarai / Anh T N Nguyen / India Cowie-Kent / Kelly O'Sullivan / Ling Yeong Chia / Hariprasad Venugopal / Celine Valant / David M Thal / Denise Wootten / Nicolas Panel / Jens Carlsson / Macdonald J Christie / Paul J White / Peter Scammells / Lauren T May / Patrick M Sexton / Radostin Danev / Yinglong Miao / Alisa Glukhova / Wendy L Imlach / Arthur Christopoulos / ![]() ![]() ![]() ![]() 要旨: The adenosine A receptor (AR) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain. However, development of analgesic orthosteric AR agonists has failed because ...The adenosine A receptor (AR) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain. However, development of analgesic orthosteric AR agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects. Here we show that [2-amino-4-(3,5-bis(trifluoromethyl)phenyl)thiophen-3-yl)(4-chlorophenyl)methanone] (MIPS521), a positive allosteric modulator of the AR, exhibits analgesic efficacy in rats in vivo through modulation of the increased levels of endogenous adenosine that occur in the spinal cord of rats with neuropathic pain. We also report the structure of the AR co-bound to adenosine, MIPS521 and a G heterotrimer, revealing an extrahelical lipid-detergent-facing allosteric binding pocket that involves transmembrane helixes 1, 6 and 7. Molecular dynamics simulations and ligand kinetic binding experiments support a mechanism whereby MIPS521 stabilizes the adenosine-receptor-G protein complex. This study provides proof of concept for structure-based allosteric drug design of non-opioid analgesic agents that are specific to disease contexts. | |||||||||
履歴 |
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構造の表示
ムービー |
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構造ビューア | EMマップ: ![]() ![]() ![]() |
添付画像 |
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ダウンロードとリンク
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マップデータ | ![]() | 6.7 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 23.5 KB 23.5 KB | 表示 表示 | ![]() |
FSC (解像度算出) | ![]() | 9.2 KB | 表示 | ![]() |
画像 | ![]() | 187.9 KB | ||
マスクデータ | ![]() | 64 MB | ![]() | |
Filedesc metadata | ![]() | 6.9 KB | ||
その他 | ![]() ![]() ![]() | 49.2 MB 49.6 MB 49.6 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
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リンク
EMDBのページ | ![]() ![]() |
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「今月の分子」の関連する項目 |
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マップ
ファイル | ![]() | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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注釈 | Final masked map | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
投影像・断面図 | 画像のコントロール
画像は Spider により作成 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 0.826 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
CCP4マップ ヘッダ情報:
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-添付データ
-マスク #1
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投影像・断面図 |
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密度ヒストグラム |
-追加マップ: Final Refine3D map
ファイル | emd_23280_additional_1.map | ||||||||||||
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注釈 | Final Refine3D map | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: Final Refine3D halfmap 1
ファイル | emd_23280_half_map_1.map | ||||||||||||
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注釈 | Final Refine3D halfmap 1 | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: Final Refine3D halfmap 1
ファイル | emd_23280_half_map_2.map | ||||||||||||
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注釈 | Final Refine3D halfmap 1 | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
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試料の構成要素
-全体 : Human adenosine A1 receptor-Gi2-protein complex bound to its endo...
全体 | 名称: Human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist adenosine |
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要素 |
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-超分子 #1: Human adenosine A1 receptor-Gi2-protein complex bound to its endo...
超分子 | 名称: Human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist adenosine タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#4 |
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由来(天然) | 生物種: ![]() |
-分子 #1: Guanine nucleotide-binding protein G(i) subunit alpha-2
分子 | 名称: Guanine nucleotide-binding protein G(i) subunit alpha-2 タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 40.502863 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MGCTVSAEDK AAAERSKMID KNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEDG YSEEECRQYR AVVYSNTIQS IMAIVKAMG NLQIDFADPS RADDARQLFA LSCTAEEQGV LPDDLSGVIR RLWADHGVQA CFGRSREYQL NDSAAYYLND L ERIAQSDY ...文字列: MGCTVSAEDK AAAERSKMID KNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEDG YSEEECRQYR AVVYSNTIQS IMAIVKAMG NLQIDFADPS RADDARQLFA LSCTAEEQGV LPDDLSGVIR RLWADHGVQA CFGRSREYQL NDSAAYYLND L ERIAQSDY IPTQQDVLRT RVKTTGIVET HFTFKDLHFK MFDVGAQRSE RKKWIHCFEG VTAIIFCVAL SAYDLVLAED EE MNRMHAS MKLFDSICNN KWFTDTSIIL FLNKKDLFEE KITHSPLTIC FPEYTGANKY DEAASYIQSK FEDLNKRKDT KEI YTHFTC STDTKNVQFV FDAVTDVIIK NNLKDCGLF UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-2 |
-分子 #2: Chimera protein of Muscarinic acetylcholine receptor M4 and Adeno...
分子 | 名称: Chimera protein of Muscarinic acetylcholine receptor M4 and Adenosine receptor A1 タイプ: protein_or_peptide / ID: 2 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 43.26102 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MKTIIALSYI FCLVFADYKD DDDAMGANFT PVNGSSGNQS VRLVTSSSLE VLFQGPPPSI SAFQAAYIGI EVLIALVSVP GNVLVIWAV KVNQALRDAT FCFIVSLAVA DVAVGALVIP LAILINIGPQ TYFHTCLMVA CPVLILTQSS ILALLAIAVD R YLRVKIPL ...文字列: MKTIIALSYI FCLVFADYKD DDDAMGANFT PVNGSSGNQS VRLVTSSSLE VLFQGPPPSI SAFQAAYIGI EVLIALVSVP GNVLVIWAV KVNQALRDAT FCFIVSLAVA DVAVGALVIP LAILINIGPQ TYFHTCLMVA CPVLILTQSS ILALLAIAVD R YLRVKIPL RYKMVVTPRR AAVAIAGCWI LSFVVGLTPM FGWNNLSAVE RAWAANGSMG EPVIKCEFEK VISMEYMVYF NF FVWVLPP LLLMVLIYLE VFYLIRKQLN KKVSASSGDP QKYYGKELKI AKSLALILFL FALSWLPLHI LNCITLFCPS CHK PSILTY IAIFLTHGNS AMNPIVYAFR IQKFRVTFLK IWNDHFRCQP APPIDEDLPE ERPDDHHHHH H UniProtKB: Muscarinic acetylcholine receptor M4, Adenosine receptor A1 |
-分子 #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
分子 | 名称: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 タイプ: protein_or_peptide / ID: 3 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 38.534062 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MHHHHHHGSS GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKL IIWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC R FLDDNQIV ...文字列: MHHHHHHGSS GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKL IIWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC R FLDDNQIV TSSGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD IN AICFFPN GNAFATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAG HDNRVS CLGVTDDGMA VATGSWDSFL KIWN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-分子 #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
分子 | 名称: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 タイプ: protein_or_peptide / ID: 4 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 7.861143 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-分子 #5: ADENOSINE
分子 | 名称: ADENOSINE / タイプ: ligand / ID: 5 / コピー数: 1 / 式: ADN |
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分子量 | 理論値: 267.241 Da |
Chemical component information | ![]() ChemComp-ADN: |
-分子 #6: {2-amino-4-[3,5-bis(trifluoromethyl)phenyl]thiophen-3-yl}(4-chlor...
分子 | 名称: {2-amino-4-[3,5-bis(trifluoromethyl)phenyl]thiophen-3-yl}(4-chlorophenyl)methanone タイプ: ligand / ID: 6 / コピー数: 1 / 式: XTD |
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分子量 | 理論値: 449.797 Da |
Chemical component information | ![]() ChemComp-XTD: |
-分子 #7: water
分子 | 名称: water / タイプ: ligand / ID: 7 / コピー数: 1 / 式: HOH |
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分子量 | 理論値: 18.015 Da |
Chemical component information | ![]() ChemComp-HOH: |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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![]() | 単粒子再構成法 |
試料の集合状態 | particle |
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試料調製
緩衝液 | pH: 7.5 |
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凍結 | 凍結剤: ETHANE-PROPANE / チャンバー内湿度: 100 % / チャンバー内温度: 277 K / 装置: FEI VITROBOT MARK IV |
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電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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撮影 | フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 検出モード: COUNTING / デジタル化 - サイズ - 横: 3838 pixel / デジタル化 - サイズ - 縦: 3710 pixel / 平均露光時間: 8.0 sec. / 平均電子線量: 50.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: ![]() |
電子光学系 | 照射モード: OTHER / 撮影モード: BRIGHT FIELD |
試料ステージ | 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER ホルダー冷却材: NITROGEN |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |