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基本情報
登録情報 | ![]() | |||||||||
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タイトル | Cryo-EM structure of neurotensin receptor 1 in complex with beta-arrestin1 and SBI-553 (complex 3) | |||||||||
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![]() | neurotensin receptor / beta-arrestin1 / phosphorylation / intracellular agonist / SBI-553 / MEMBRANE PROTEIN | |||||||||
機能・相同性 | ![]() G protein-coupled neurotensin receptor activity / inositol phosphate catabolic process / symmetric synapse / angiotensin receptor binding / positive regulation of gamma-aminobutyric acid secretion / D-aspartate import across plasma membrane / TGFBR3 regulates TGF-beta signaling / Activation of SMO / regulation of membrane depolarization / negative regulation of interleukin-8 production ...G protein-coupled neurotensin receptor activity / inositol phosphate catabolic process / symmetric synapse / angiotensin receptor binding / positive regulation of gamma-aminobutyric acid secretion / D-aspartate import across plasma membrane / TGFBR3 regulates TGF-beta signaling / Activation of SMO / regulation of membrane depolarization / negative regulation of interleukin-8 production / positive regulation of arachidonate secretion / L-glutamate import across plasma membrane / regulation of respiratory gaseous exchange / positive regulation of inhibitory postsynaptic potential / G protein-coupled receptor internalization / arrestin family protein binding / negative regulation of systemic arterial blood pressure / negative regulation of release of sequestered calcium ion into cytosol / positive regulation of glutamate secretion / negative regulation of NF-kappaB transcription factor activity / positive regulation of inositol phosphate biosynthetic process / Lysosome Vesicle Biogenesis / response to lipid / temperature homeostasis / positive regulation of cardiac muscle hypertrophy / Golgi Associated Vesicle Biogenesis / stress fiber assembly / positive regulation of Rho protein signal transduction / pseudopodium / detection of temperature stimulus involved in sensory perception of pain / negative regulation of interleukin-6 production / positive regulation of receptor internalization / enzyme inhibitor activity / negative regulation of Notch signaling pathway / neuropeptide signaling pathway / Activated NOTCH1 Transmits Signal to the Nucleus / insulin-like growth factor receptor binding / clathrin-coated pit / negative regulation of protein ubiquitination / GTPase activator activity / cytoplasmic vesicle membrane / positive regulation of release of sequestered calcium ion into cytosol / Peptide ligand-binding receptors / adult locomotory behavior / dendritic shaft / learning / G protein-coupled receptor activity / electron transport chain / Signaling by high-kinase activity BRAF mutants / G protein-coupled receptor binding / MAP2K and MAPK activation / cytoplasmic side of plasma membrane / endocytic vesicle membrane / positive regulation of protein phosphorylation / terminal bouton / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Cargo recognition for clathrin-mediated endocytosis / Signaling by BRAF and RAF1 fusions / Clathrin-mediated endocytosis / protein transport / Thrombin signalling through proteinase activated receptors (PARs) / ubiquitin-dependent protein catabolic process / cytoplasmic vesicle / perikaryon / G alpha (s) signalling events / molecular adaptor activity / chemical synaptic transmission / G alpha (q) signalling events / dendritic spine / proteasome-mediated ubiquitin-dependent protein catabolic process / periplasmic space / transcription coactivator activity / electron transfer activity / positive regulation of ERK1 and ERK2 cascade / Ub-specific processing proteases / protein ubiquitination / nuclear body / positive regulation of apoptotic process / G protein-coupled receptor signaling pathway / membrane raft / iron ion binding / Golgi membrane / lysosomal membrane / ubiquitin protein ligase binding / heme binding / positive regulation of gene expression / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / chromatin / protein-containing complex binding / cell surface / endoplasmic reticulum / Golgi apparatus / signal transduction / positive regulation of transcription by RNA polymerase II / nucleoplasm / identical protein binding 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: 2.65 Å | |||||||||
![]() | Sun D / Li X / Yuan Q / Yin W / Xu HE / Tian C | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Molecular mechanism of the arrestin-biased agonism of neurotensin receptor 1 by an intracellular allosteric modulator. 著者: Demeng Sun / Xiang Li / Qingning Yuan / Yuanxia Wang / Pan Shi / Huanhuan Zhang / Tao Wang / Wenjing Sun / Shenglong Ling / Yuanchun Liu / Jinglin Lai / Wenqin Xie / Wanchao Yin / Lei Liu / H ...著者: Demeng Sun / Xiang Li / Qingning Yuan / Yuanxia Wang / Pan Shi / Huanhuan Zhang / Tao Wang / Wenjing Sun / Shenglong Ling / Yuanchun Liu / Jinglin Lai / Wenqin Xie / Wanchao Yin / Lei Liu / H Eric Xu / Changlin Tian / ![]() 要旨: Biased allosteric modulators (BAMs) of G protein-coupled receptors (GPCRs) have been at the forefront of drug discovery owing to their potential to selectively stimulate therapeutically relevant ...Biased allosteric modulators (BAMs) of G protein-coupled receptors (GPCRs) have been at the forefront of drug discovery owing to their potential to selectively stimulate therapeutically relevant signaling and avoid on-target side effects. Although structures of GPCRs in complex with G protein or GRK in a BAM-bound state have recently been resolved, revealing that BAM can induce biased signaling by directly modulating interactions between GPCRs and these two transducers, no BAM-bound GPCR-arrestin complex structure has yet been determined, limiting our understanding of the full pharmacological profile of BAMs. Herein, we developed a chemical protein synthesis strategy to generate neurotensin receptor 1 (NTSR1) with defined hexa-phosphorylation at its C-terminus and resolved high-resolution cryo-EM structures (2.65-2.88 Å) of NTSR1 in complex with both β-arrestin1 and the BAM SBI-553. These structures revealed a unique "loop engagement" configuration of β-arrestin1 coupling to NTSR1 in the presence of SBI-553, markedly different from the typical "core engagement" configuration observed in the absence of BAMs. This configuration is characterized by the engagement of the intracellular loop 3 of NTSR1 with a cavity in the central crest of β-arrestin1, representing a previously unobserved, arrestin-selective conformation of GPCR. Our findings fill the critical knowledge gap regarding the regulation of GPCR-arrestin interactions and biased signaling by BAMs, which would advance the development of safer and more efficacious GPCR-targeted therapeutics. | |||||||||
履歴 |
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構造の表示
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マップデータ | ![]() | 167.9 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 23.3 KB 23.3 KB | 表示 表示 | ![]() |
画像 | ![]() | 105.3 KB | ||
Filedesc metadata | ![]() | 7.7 KB | ||
その他 | ![]() ![]() | 165.4 MB 165.4 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-検証レポート
文書・要旨 | ![]() | 806 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 805.6 KB | 表示 | |
XML形式データ | ![]() | 15.1 KB | 表示 | |
CIF形式データ | ![]() | 18 KB | 表示 | |
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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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: 0.824 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
-ハーフマップ: #1
ファイル | emd_60578_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: #2
ファイル | emd_60578_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 |
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試料の構成要素
-全体 : NTSR1-beta-arrestin1 complex
全体 | 名称: NTSR1-beta-arrestin1 complex |
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要素 |
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-超分子 #1: NTSR1-beta-arrestin1 complex
超分子 | 名称: NTSR1-beta-arrestin1 complex / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#5 詳細: NTSR1 in complex with beat-arrestin1 and the arrestin-biased intracellular agonist SBI-553 |
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由来(天然) | 生物種: ![]() |
-分子 #1: Beta-arrestin-1
分子 | 名称: Beta-arrestin-1 / タイプ: protein_or_peptide / ID: 1 詳細: Human beta-arrestin1 was truncated at residues 382 to remove autoinhibition and added His tag at its N-terminus. 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: 45.224598 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MGSHHHHHHH HGSLEVLFQG PGDKGTRVFK KASPNGKLTV YLGKRDFVDH IDLVDPVDGV VLVDPEYLKE RRVYVTLTCA FRYGREDLD VLGLTFRKDL FVANVQSFPP APEDKKPLTR LQERLIKKLG EHAYPFTFEI PPNLPCSVTL QPGPEDTGKA C GVDYEVKA ...文字列: MGSHHHHHHH HGSLEVLFQG PGDKGTRVFK KASPNGKLTV YLGKRDFVDH IDLVDPVDGV VLVDPEYLKE RRVYVTLTCA FRYGREDLD VLGLTFRKDL FVANVQSFPP APEDKKPLTR LQERLIKKLG EHAYPFTFEI PPNLPCSVTL QPGPEDTGKA C GVDYEVKA FCAENLEEKI HKRNSVRLVI RKVQYAPERP GPQPTAETTR QFLMSDKPLH LEASLDKEIY YHGEPISVNV HV TNNTNKT VKKIKISVRQ YADICLFNTA QYKCPVAMEE ADDTVAPSST FCKVYTLTPF LANNREKRGL ALDGKLKHED TNL ASSTLL REGANREILG IIVSYKVKVK LVVSRGGLLG DLASSDVAVE LPFTLMHPKP KEEPPHREVP ENETPVDTNL IELD TN UniProtKB: Beta-arrestin-1 |
-分子 #2: Fab30 heavy chain
分子 | 名称: Fab30 heavy chain / タイプ: protein_or_peptide / ID: 2 詳細: The heavy chain of antibody fragment Fab30 wasmodified with a GP64 secretion signal peptide at the N-terminus, and His tag at the C-terminus. 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: 27.72701 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MVSAIVLYVL LAAAAHSAFA EISEVQLVES GGGLVQPGGS LRLSCAASGF NVYSSSIHWV RQAPGKGLEW VASISSYYGY TYYADSVKG RFTISADTSK NTAYLQMNSL RAEDTAVYYC ARSRQFWYSG LDYWGQGTLV TVSSASTKGP SVFPLAPSSK S TSGGTAAL ...文字列: MVSAIVLYVL LAAAAHSAFA EISEVQLVES GGGLVQPGGS LRLSCAASGF NVYSSSIHWV RQAPGKGLEW VASISSYYGY TYYADSVKG RFTISADTSK NTAYLQMNSL RAEDTAVYYC ARSRQFWYSG LDYWGQGTLV TVSSASTKGP SVFPLAPSSK S TSGGTAAL GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS LGTQTYICNV NHKPSNTKVD KK VEPKSCD KTAAAHHHHH HHH |
-分子 #3: Fab30 light chain
分子 | 名称: Fab30 light chain / タイプ: protein_or_peptide / ID: 3 詳細: The heavy chain of antibody fragment Fab30 wasmodified with a GP64 secretion signal peptide at the N-terminus 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: 25.436492 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MVSAIVLYVL LAAAAHSAFA SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSG TDFTLTISSL QPEDFATYYC QQYKYVPVTF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN F YPREAKVQ ...文字列: MVSAIVLYVL LAAAAHSAFA SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSG TDFTLTISSL QPEDFATYYC QQYKYVPVTF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN F YPREAKVQ WKVDNALQSG NSQESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC |
-分子 #4: Soluble cytochrome b562,Neurotensin receptor type 1
分子 | 名称: Soluble cytochrome b562,Neurotensin receptor type 1 / 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: 62.097848 KDa |
組換発現 | 生物種: Mammalian expression vector Flag-MCS-pcDNA3.1 (その他) |
配列 | 文字列: MKTIIALSYI FCLVFAGSAD LEDNWETLND NLKVIEKADN AAQVKDALTK MRAAALDAQK ATPPKLEDKS PDSPEMKDFR HGFDILVGQ IDDALKLANE GKVKEAQAAA EQLKTTRNAY IQKYLASGSL EVLFQGPMRL NSSAPGTPGT PAADPFQRAQ A GLEEALLA ...文字列: MKTIIALSYI FCLVFAGSAD LEDNWETLND NLKVIEKADN AAQVKDALTK MRAAALDAQK ATPPKLEDKS PDSPEMKDFR HGFDILVGQ IDDALKLANE GKVKEAQAAA EQLKTTRNAY IQKYLASGSL EVLFQGPMRL NSSAPGTPGT PAADPFQRAQ A GLEEALLA PGFGNASGNA SERVLAAPSS ELDVNTDIYS KVLVTAVYLA LFVVGTVGNT VTAFTLARKK SLQSLQSTVH YH LGSLALS DLLTLLLAMP VELYNFIWVH HPWAFGDAGC RGYYFLRDAC TYATALNVAS LSVERYLALC HPFKAKTLMS RSR TKKFIS AIWLASALLA VPMLFTMGEQ NRSADGQHAG GLVCTPTIHT ATVKVVIQVN TFMSFIFPMV VISVLNTIIA NKLT VMVRQ AAEQGQVCTV GGEHSTFSMA IEPGRVQALR HGVRVLRAVV IAFVVCWLPY HVRRLMFCYI SDEQWTPFLY DFYHY FYMV TNALFYVSST INPILYNLVS ANFRHIFIAT LACLCPVWRR RRKRPCFNAF SRKCD(SEP)V(SEP)(SEP)N H (TPO)L(SEP)(SEP)NATR ETLY UniProtKB: Soluble cytochrome b562, Neurotensin receptor type 1 |
-分子 #5: neurotensin peptide 8-13
分子 | 名称: neurotensin peptide 8-13 / タイプ: protein_or_peptide / ID: 5 / 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: 819.007 Da |
配列 | 文字列: RRPYIL |
-分子 #6: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(o...
分子 | 名称: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate タイプ: ligand / ID: 6 / コピー数: 1 / 式: PIO |
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分子量 | 理論値: 746.566 Da |
Chemical component information | ![]() ChemComp-PIO: |
-分子 #7: 2-[{2-(1-fluorocyclopropyl)-4-[4-(2-methoxyphenyl)piperidin-1-yl]...
分子 | 名称: 2-[{2-(1-fluorocyclopropyl)-4-[4-(2-methoxyphenyl)piperidin-1-yl]quinazolin-6-yl}(methyl)amino]ethan-1-ol タイプ: ligand / ID: 7 / コピー数: 1 / 式: SRW |
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分子量 | 理論値: 450.548 Da |
Chemical component information | ![]() ChemComp-SRW: |
-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
濃度 | 1.0 mg/mL |
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緩衝液 | pH: 7.4 |
凍結 | 凍結剤: ETHANE |
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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 BIOQUANTUM (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): 2.0 µm / 最小 デフォーカス(公称値): 0.8 µm |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |