+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-41268 | |||||||||
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タイトル | Cryo-EM structure of epinephrine-bound alpha-1A-adrenergic receptor in complex with heterotrimeric Gq-protein | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | Alpha-1A-adrenergic receptor / Epinephrine / SIGNALING PROTEIN | |||||||||
機能・相同性 | 機能・相同性情報 negative regulation of heart rate involved in baroreceptor response to increased systemic arterial blood pressure / alpha1-adrenergic receptor activity / positive regulation of heart rate by epinephrine-norepinephrine / positive regulation of the force of heart contraction by epinephrine-norepinephrine / norepinephrine-epinephrine vasoconstriction involved in regulation of systemic arterial blood pressure / pilomotor reflex / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process / neuron-glial cell signaling / cell growth involved in cardiac muscle cell development / positive regulation of protein kinase C signaling ...negative regulation of heart rate involved in baroreceptor response to increased systemic arterial blood pressure / alpha1-adrenergic receptor activity / positive regulation of heart rate by epinephrine-norepinephrine / positive regulation of the force of heart contraction by epinephrine-norepinephrine / norepinephrine-epinephrine vasoconstriction involved in regulation of systemic arterial blood pressure / pilomotor reflex / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process / neuron-glial cell signaling / cell growth involved in cardiac muscle cell development / positive regulation of protein kinase C signaling / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / positive regulation of action potential / G protein-coupled adenosine receptor signaling pathway / PLC beta mediated events / negative regulation of calcium ion-dependent exocytosis / phospholipase C-activating dopamine receptor signaling pathway / entrainment of circadian clock / regulation of platelet activation / positive regulation of smooth muscle contraction / positive regulation of urine volume / phototransduction, visible light / negative regulation of adenylate cyclase activity / adult heart development / positive regulation of neural precursor cell proliferation / calcium ion transport into cytosol / gamma-aminobutyric acid signaling pathway / negative regulation of synaptic transmission / regulation of canonical Wnt signaling pathway / Adrenoceptors / glutamate receptor signaling pathway / action potential / positive regulation of cardiac muscle hypertrophy / neuronal dense core vesicle / PKA activation in glucagon signalling / regulation of calcium ion transport / negative regulation of apoptotic signaling pathway / hair follicle placode formation / developmental growth / smooth muscle contraction / photoreceptor outer segment / D1 dopamine receptor binding / intracellular transport / Adenylate cyclase inhibitory pathway / renal water homeostasis / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / positive regulation of insulin receptor signaling pathway / viral release from host cell by cytolysis / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of vasoconstriction / cellular response to glucagon stimulus / positive regulation of cardiac muscle contraction / adenylate cyclase activator activity / regulation of insulin secretion / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / peptidoglycan catabolic process / response to hormone / GTPase activator activity / negative regulation of autophagy / response to nutrient / positive regulation of superoxide anion generation / trans-Golgi network membrane / positive regulation of synaptic transmission, GABAergic / Regulation of insulin secretion / G protein-coupled receptor binding / negative regulation of inflammatory response to antigenic stimulus / negative regulation of protein kinase activity / bone development / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / caveola / Activation of the phototransduction cascade / adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 activity / G-protein activation / platelet aggregation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / cognition / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / 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 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.1 Å | |||||||||
データ登録者 | Su M / Huang XY | |||||||||
資金援助 | 米国, 2件
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引用 | ジャーナル: Nat Commun / 年: 2023 タイトル: Structural basis of agonist specificity of α-adrenergic receptor. 著者: Minfei Su / Jinan Wang / Guoqing Xiang / Hung Nguyen Do / Joshua Levitz / Yinglong Miao / Xin-Yun Huang / 要旨: α-adrenergic receptors (α-ARs) play critical roles in the cardiovascular and nervous systems where they regulate blood pressure, cognition, and metabolism. However, the lack of specific agonists ...α-adrenergic receptors (α-ARs) play critical roles in the cardiovascular and nervous systems where they regulate blood pressure, cognition, and metabolism. However, the lack of specific agonists for all α subtypes has limited our understanding of the physiological roles of different α-AR subtypes, and led to the stagnancy in agonist-based drug development for these receptors. Here we report cryo-EM structures of α-AR in complex with heterotrimeric G-proteins and either the endogenous common agonist epinephrine or the α-AR-specific synthetic agonist A61603. These structures provide molecular insights into the mechanisms underlying the discrimination between α-AR and α-AR by A61603. Guided by the structures and corresponding molecular dynamics simulations, we engineer α-AR mutants that are not responsive to A61603, and α-AR mutants that can be potently activated by A61603. Together, these findings advance our understanding of the agonist specificity for α-ARs at the molecular level, opening the possibility of rational design of subtype-specific agonists. | |||||||||
履歴 |
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-構造の表示
添付画像 |
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-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_41268.map.gz | 64.2 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-41268-v30.xml emd-41268.xml | 21.9 KB 21.9 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_41268.png | 63.2 KB | ||
Filedesc metadata | emd-41268.cif.gz | 6.6 KB | ||
その他 | emd_41268_additional_1.map.gz emd_41268_half_map_1.map.gz emd_41268_half_map_2.map.gz | 33.1 MB 59.4 MB 59.4 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-41268 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-41268 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_41268_validation.pdf.gz | 783.2 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_41268_full_validation.pdf.gz | 782.8 KB | 表示 | |
XML形式データ | emd_41268_validation.xml.gz | 13.1 KB | 表示 | |
CIF形式データ | emd_41268_validation.cif.gz | 15.2 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-41268 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-41268 | HTTPS FTP |
-関連構造データ
関連構造データ | 8thlMC 8thkC M: このマップから作成された原子モデル 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
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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「今月の分子」の関連する項目 |
-マップ
ファイル | ダウンロード / ファイル: emd_41268.map.gz / 形式: CCP4 / 大きさ: 125 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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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: 0.8608 Å | ||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
-追加マップ: Receptor and Ga focused map
ファイル | emd_41268_additional_1.map | ||||||||||||
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注釈 | Receptor and Ga focused 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: #2
ファイル | emd_41268_half_map_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: #1
ファイル | emd_41268_half_map_2.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-試料の構成要素
-全体 : Epinephrine-bound alpha-1A-adrenergic receptor in complex with he...
全体 | 名称: Epinephrine-bound alpha-1A-adrenergic receptor in complex with heterotrimeric Gq-protein |
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要素 |
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-超分子 #1: Epinephrine-bound alpha-1A-adrenergic receptor in complex with he...
超分子 | 名称: Epinephrine-bound alpha-1A-adrenergic receptor in complex with heterotrimeric Gq-protein タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#5 |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 160 KDa |
-分子 #1: Guanine nucleotide-binding protein G(i) subunit alpha-2,Guanine n...
分子 | 名称: Guanine nucleotide-binding protein G(i) subunit alpha-2,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,Guanine nucleotide-binding protein G(q) subunit alpha 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: Homo sapiens (ヒト) |
分子量 | 理論値: 28.084832 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA ...文字列: MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA RYTTPEDATP EPGEDPRVTR AKYFIRKEFV DISTASGDGR HICYPHFTCA VDTENARRIF NDCKDIILQM NL REYNLV UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-2, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(q) subunit alpha |
-分子 #2: 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: 2 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 39.418086 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR ...文字列: MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR FLDDNQIVTS SGDTTCALWD IETGQQTTTF TGHTGDVMSL SLAPDTRLFV SGACDASAKL WDVREGMCRQ TF TGHESDI NAICFFPNGN AFATGSDDAT CRLFDLRADQ ELMTYSHDNI ICGITSVSFS KSGRLLLAGY DDFNCNVWDA LKA DRAGVL AGHDNRVSCL GVTDDGMAVA TGSWDSFLKI WN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-分子 #3: 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: 3 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 7.861143 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
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 #4: Single fab chain (scFv16)
分子 | 名称: Single fab chain (scFv16) / 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: Homo sapiens (ヒト) |
分子量 | 理論値: 28.668922 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...文字列: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL KAAALEVLFQ GPHHHHHHHH |
-分子 #5: Endolysin,Alpha-1A adrenergic receptor
分子 | 名称: Endolysin,Alpha-1A adrenergic receptor / タイプ: protein_or_peptide / ID: 5 / コピー数: 1 / 光学異性体: LEVO / EC番号: lysozyme |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 56.485246 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: MKTIIALSYI FCLVFADYKD DDDKNIFEML RIDEGLRLKI YKDTEGYYTI GIGHLLTKSP SLNAAKSELD KAIGRNTNGV ITKDEAEKL FNQDVDAAVR GILRNAKLKP VYDSLDAVRR AALINMVFQM GETGVAGFTN SLRMLQQKRW DEAAVNLAKS R WYNQTPNR ...文字列: MKTIIALSYI FCLVFADYKD DDDKNIFEML RIDEGLRLKI YKDTEGYYTI GIGHLLTKSP SLNAAKSELD KAIGRNTNGV ITKDEAEKL FNQDVDAAVR GILRNAKLKP VYDSLDAVRR AALINMVFQM GETGVAGFTN SLRMLQQKRW DEAAVNLAKS R WYNQTPNR AKRVITTFRT GTWDAYAAAT QPPAPVNISK AILLGVILGG LILFGVLGNI LVILSVACHR HLHSVTHYYI VN LAVADLL LTSTVLPFSA IFEVLGYWAF GRVFCNIWAA VDVLCCTASI MGLCIISIDR YIGVSYPLRY PTIVTQRRGL MAL LCVWAL SLVISIGPLF GWRQPAPEDE TICQINEEPG YVLFSALGSF YLPLAIILVM YCRVYVVAKR ESRGLKSGLK TDKS HFSVR LLKFSREKKA AKTLGIVVGC FVLCWLPFFL VMPIGSFFPD FKPSETVFKI VFWLGYLNSC INPIIYPCSS QEFKK AFQN VLRIQCLCRK QASLEVLFQ UniProtKB: Endolysin, Alpha-1A adrenergic receptor |
-分子 #6: L-EPINEPHRINE
分子 | 名称: L-EPINEPHRINE / タイプ: ligand / ID: 6 / コピー数: 1 / 式: ALE |
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分子量 | 理論値: 183.204 Da |
Chemical component information | ChemComp-ALE: |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
濃度 | 2.5 mg/mL |
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緩衝液 | pH: 7 |
凍結 | 凍結剤: ETHANE / 装置: FEI VITROBOT MARK IV |
-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) / 平均電子線量: 52.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 1.8 µm / 最小 デフォーカス(公称値): 1.0 µm |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
-画像解析
初期モデル | モデルのタイプ: PDB ENTRY PDBモデル - PDB ID: |
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最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 3.1 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 219834 |
初期 角度割当 | タイプ: MAXIMUM LIKELIHOOD |
最終 角度割当 | タイプ: MAXIMUM LIKELIHOOD |