+
データを開く
-
基本情報
登録情報 | ![]() | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
タイトル | Epinephrine-activated human beta3 adrenergic receptor | |||||||||
![]() | ||||||||||
![]() |
| |||||||||
![]() | Complex / beta3AR / MEMBRANE PROTEIN/IMMUNE SYSTEM / MEMBRANE PROTEIN-IMMUNE SYSTEM complex | |||||||||
機能・相同性 | ![]() beta-3 adrenergic receptor binding / beta3-adrenergic receptor activity / beta-adrenergic receptor activity / epinephrine binding / sensory perception of chemical stimulus / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / energy reserve metabolic process / G-protein activation / Activation of the phototransduction cascade ...beta-3 adrenergic receptor binding / beta3-adrenergic receptor activity / beta-adrenergic receptor activity / epinephrine binding / sensory perception of chemical stimulus / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / energy reserve metabolic process / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (i) signalling events / 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 / norepinephrine binding / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / alkylglycerophosphoethanolamine phosphodiesterase activity / Adrenoceptors / heat generation / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / 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 / beta-2 adrenergic receptor binding / G alpha (s) signalling events / G alpha (q) signalling events / photoreceptor outer segment membrane / G alpha (i) signalling events / negative regulation of multicellular organism growth / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / eating behavior / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / diet induced thermogenesis / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / photoreceptor outer segment / D1 dopamine receptor binding / generation of precursor metabolites and energy / adenylate cyclase-activating adrenergic receptor signaling pathway / brown fat cell differentiation / cardiac muscle cell apoptotic process / insulin-like growth factor receptor binding / adenylate cyclase activator activity / ionotropic glutamate receptor binding / photoreceptor inner segment / response to cold / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / cellular response to catecholamine stimulus / sensory perception of taste / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / GTPase binding / retina development in camera-type eye / cellular response to hypoxia / positive regulation of cold-induced thermogenesis / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / cell body / G alpha (s) signalling events / receptor complex / cell population proliferation / positive regulation of MAPK cascade / carbohydrate metabolic process / G protein-coupled receptor signaling pathway / GTPase activity / dendrite 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: 2.34 Å | |||||||||
![]() | Zheng S / Zhang S / Dai S / Chen K / Gao K / Lin B / Liu X | |||||||||
資金援助 | ![]()
| |||||||||
![]() | ![]() タイトル: Molecular Mechanism of the β3AR Agonist Activity of a β-Blocker. 著者: Shuang Zheng / Shuhao Zhang / Shengjie Dai / Kai Chen / Kaixuan Gao / Xiaoou Sun / Bin Lin / Xiangyu Liu / ![]() 要旨: Development of subtype-selective drugs for G protein-coupled receptors poses a significant challenge due to high similarity between subtypes, as exemplified by the three β-adrenergic receptors ...Development of subtype-selective drugs for G protein-coupled receptors poses a significant challenge due to high similarity between subtypes, as exemplified by the three β-adrenergic receptors (βARs). The β3AR agonists show promise for treating the overactive bladder or preterm birth, but their potential is hindered by off-target activation of β1AR and β2AR. Interestingly, several β-blockers, which are antagonists of the β1ARs and β2ARs, have been reported to exhibit agonist activity at the β3AR. However, the molecular mechanism remains elusive. Understanding the underlying mechanism should facilitate the development of β3AR agonist drugs with improved selectivity and reduced off-target effects. In this work, we determined the structures of human β3AR in complex with the endogenous agonist epinephrine or with a synthetic β3AR agonist carazolol, which is also a high-affinity β-blocker. Structure comparison, mutagenesis studies and molecular dynamics simulations revealed that the differences on the flexibility of D3.32 directly contribute to carazolol's distinct activities as an antagonist for the β2AR and an agonist for the β3AR. The process is also indirectly influenced by the extracellular loops (ECL), especially ECL1. Taken together, these results provide key guidance for development of selective β3AR agonists, paving the way for new therapeutic opportunities. | |||||||||
履歴 |
|
-
構造の表示
添付画像 |
---|
-
ダウンロードとリンク
-EMDBアーカイブ
マップデータ | ![]() | 42.7 MB | ![]() | |
---|---|---|---|---|
ヘッダ (付随情報) | ![]() ![]() | 20.5 KB 20.5 KB | 表示 表示 | ![]() |
画像 | ![]() | 87.7 KB | ||
Filedesc metadata | ![]() | 6.6 KB | ||
その他 | ![]() ![]() | 42 MB 42 MB | ||
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 | ![]() 9ijeMC ![]() 9ijdC ![]() 39845 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 ( |
---|---|
類似構造データ | 類似検索 - 機能・相同性 ![]() |
-
リンク
EMDBのページ | ![]() ![]() |
---|---|
「今月の分子」の関連する項目 |
-
マップ
ファイル | ![]() | ||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
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: 1.0825 Å | ||||||||||||||||||||||||||||||||||||
密度 |
| ||||||||||||||||||||||||||||||||||||
対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
|
-添付データ
-ハーフマップ: #2
ファイル | emd_60629_half_map_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
投影像・断面図 |
| ||||||||||||
密度ヒストグラム |
-ハーフマップ: #1
ファイル | emd_60629_half_map_2.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
投影像・断面図 |
| ||||||||||||
密度ヒストグラム |
-
試料の構成要素
-全体 : Epinephrine bounded human beta3 adrenergic receptor-Gs protein co...
全体 | 名称: Epinephrine bounded human beta3 adrenergic receptor-Gs protein complex with Gbeta, Ggamma, Nb35 and scFv16 |
---|---|
要素 |
|
-超分子 #1: Epinephrine bounded human beta3 adrenergic receptor-Gs protein co...
超分子 | 名称: Epinephrine bounded human beta3 adrenergic receptor-Gs protein complex with Gbeta, Ggamma, Nb35 and scFv16 タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#6 |
---|---|
由来(天然) | 生物種: ![]() |
-分子 #1: 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: 1 / コピー数: 1 / 光学異性体: LEVO |
---|---|
由来(天然) | 生物種: ![]() ![]() |
分子量 | 理論値: 37.413863 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: QSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...文字列: QSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD INAICFFPNG NA FATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGV TDDGMA VATGSWDSFL KIWN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-分子 #2: Camelid antibody VHH fragment
分子 | 名称: Camelid antibody VHH fragment / タイプ: protein_or_peptide / ID: 2 / コピー数: 1 / 光学異性体: LEVO |
---|---|
由来(天然) | 生物種: ![]() ![]() |
分子量 | 理論値: 13.885439 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPE DTAVYYCARC PAPFTRDCFD VTSTTYAYRG QGTQVTVSS |
-分子 #3: Single-chain Fv16
分子 | 名称: Single-chain Fv16 / タイプ: protein_or_peptide / ID: 3 / コピー数: 1 / 光学異性体: LEVO |
---|---|
由来(天然) | 生物種: ![]() |
分子量 | 理論値: 26.206219 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS SGGGGSGGGG SGGGGADIVM TQATSSVPVT PGESVSISCR S SKSLLHSN ...文字列: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS SGGGGSGGGG SGGGGADIVM TQATSSVPVT PGESVSISCR S SKSLLHSN GNTYLYWFLQ RPGQSPQLLI YRMSNLASGV PDRFSGSGSG TAFTLTISRL EAEDVGVYYC MQHLEYPLTF GA GTKLEL |
-分子 #4: Beta-3 adrenergic receptor
分子 | 名称: Beta-3 adrenergic receptor / タイプ: protein_or_peptide / ID: 4 / コピー数: 1 / 光学異性体: LEVO |
---|---|
由来(天然) | 生物種: ![]() |
分子量 | 理論値: 34.64702 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: ALLALAVLAT VGGNLLVIVA IAWTPRLQTM TNVFVTSLAA ADLVMGLLVV PPAATLALTG HWPLGATGCE LWTSVDVLCV TASIWTLCA LAVDRYLAVT NPLRYGALVT KRCARTAVVL VWVVSAAVSF APIMSQWWRV GADAEAQRCH SNPRCCAFAS N MPYVLLSS ...文字列: ALLALAVLAT VGGNLLVIVA IAWTPRLQTM TNVFVTSLAA ADLVMGLLVV PPAATLALTG HWPLGATGCE LWTSVDVLCV TASIWTLCA LAVDRYLAVT NPLRYGALVT KRCARTAVVL VWVVSAAVSF APIMSQWWRV GADAEAQRCH SNPRCCAFAS N MPYVLLSS SVSFYLPLLV MLFVYARVFV VATRQLRLLR GELGRFPPEE SPPAPSRSLA PAPVGTCAPP EGVPACGRRP AR LLPLREH RALCTLGLIM GTFTLCWLPF FLANVLRALG GPSLVPGPAF LALNWLGYAN SAFNPLIYCR SPDFRSAFRR LLC R UniProtKB: Beta-3 adrenergic receptor |
-分子 #5: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
分子 | 名称: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short タイプ: protein_or_peptide / ID: 5 / コピー数: 1 / 光学異性体: LEVO |
---|---|
由来(天然) | 生物種: ![]() ![]() |
分子量 | 理論値: 43.320797 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: LSAEDKAAVE RSKMIEKQLQ KDKQVYRATH RLLLLGADNS GKSTIVKQMR ILHVNGFNGE GGEEDPQAAR SNSDGEKATK VQDIKNNLK EAIETIVAAM SNLVPPVELA NPENQFRVDY ILSVMNVPDF DFPPEFYEHA KALWEDEGVR ACYERSNEYQ L IDCAQYFL ...文字列: LSAEDKAAVE RSKMIEKQLQ KDKQVYRATH RLLLLGADNS GKSTIVKQMR ILHVNGFNGE GGEEDPQAAR SNSDGEKATK VQDIKNNLK EAIETIVAAM SNLVPPVELA NPENQFRVDY ILSVMNVPDF DFPPEFYEHA KALWEDEGVR ACYERSNEYQ L IDCAQYFL DKIDVIKQDD YVPSDQDLLR CRVLTSGIFE TKFQVDKVNF HMFDVGGQRD ERRKWIQCFN DVTAIIFVVD SS DYNRLQE ALNLFKSIWN NRWLRTISVI LFLNKQDLLA EKVLAGKSKI EDYFPEFARY TTPEDATPEP GEDPRVTRAK YFI RDEFLR ISTASGDGRH YCYPHFTCAV DTENARRIFN DCRDIIQRMH LRQYELL UniProtKB: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short |
-分子 #6: 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: 6 / コピー数: 1 / 光学異性体: LEVO |
---|---|
由来(天然) | 生物種: ![]() ![]() |
分子量 | 理論値: 5.731619 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: AQARKLVEQL KMEANIDRIK VSKAAADLMA YCEAHAKEDP LLTPVPASEN PF UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-分子 #7: L-EPINEPHRINE
分子 | 名称: L-EPINEPHRINE / タイプ: ligand / ID: 7 / コピー数: 1 / 式: ALE |
---|---|
分子量 | 理論値: 183.204 Da |
Chemical component information | ![]() ChemComp-ALE: |
-分子 #8: water
分子 | 名称: water / タイプ: ligand / ID: 8 / コピー数: 1 / 式: HOH |
---|---|
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 |
---|---|
![]() | 単粒子再構成法 |
試料の集合状態 | particle |
-
試料調製
緩衝液 | pH: 8 |
---|---|
凍結 | 凍結剤: ETHANE |
-
電子顕微鏡法
顕微鏡 | FEI TITAN |
---|---|
撮影 | フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 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: FLOOD BEAM / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 1.5 µm / 最小 デフォーカス(公称値): 1.1 µm |
-
画像解析
初期モデル | モデルのタイプ: NONE |
---|---|
最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 2.34 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 1423878 |
初期 角度割当 | タイプ: MAXIMUM LIKELIHOOD |
最終 角度割当 | タイプ: MAXIMUM LIKELIHOOD |