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基本情報
登録情報 | ![]() | |||||||||
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タイトル | CryoEM structure of Go-coupled NTSR1 | |||||||||
![]() | CryoEM structure of Go-coupled NTSR1 | |||||||||
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![]() | GPCR / neurotensin receptor / allosterism / SBI-553 / MEMBRANE PROTEIN | |||||||||
機能・相同性 | ![]() response to antipsychotic drug / response to mineralocorticoid / regulation of locomotion involved in locomotory behavior / Peptide ligand-binding receptors / positive regulation of locomotion / neuropeptide receptor binding / G protein-coupled neurotensin receptor activity / regulation of inositol trisphosphate biosynthetic process / inositol phosphate catabolic process / symmetric synapse ...response to antipsychotic drug / response to mineralocorticoid / regulation of locomotion involved in locomotory behavior / Peptide ligand-binding receptors / positive regulation of locomotion / neuropeptide receptor binding / G protein-coupled neurotensin receptor activity / regulation of inositol trisphosphate biosynthetic process / inositol phosphate catabolic process / symmetric synapse / D-aspartate import across plasma membrane / positive regulation of gamma-aminobutyric acid secretion / regulation of membrane depolarization / positive regulation of arachidonate secretion / vocalization behavior / neuron spine / L-glutamate import across plasma membrane / mu-type opioid receptor binding / regulation of behavioral fear response / regulation of respiratory gaseous exchange / corticotropin-releasing hormone receptor 1 binding / neuropeptide hormone activity / cAMP biosynthetic process / positive regulation of inhibitory postsynaptic potential / negative regulation of systemic arterial blood pressure / conditioned place preference / positive regulation of glutamate secretion / vesicle docking involved in exocytosis / negative regulation of release of sequestered calcium ion into cytosol / digestive tract development / G alpha (q) signalling events / hyperosmotic response / G protein-coupled dopamine receptor signaling pathway / response to food / positive regulation of inositol phosphate biosynthetic process / response to lipid / response to corticosterone / cellular response to lithium ion / temperature homeostasis / regulation of heart contraction / response to stress / parallel fiber to Purkinje cell synapse / detection of temperature stimulus involved in sensory perception of pain / associative learning / neuropeptide signaling pathway / postsynaptic modulation of chemical synaptic transmission / response to axon injury / transport vesicle / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / axon terminus / cellular response to dexamethasone stimulus / response to amphetamine / muscle contraction / positive regulation of release of sequestered calcium ion into cytosol / liver development / blood vessel diameter maintenance / adult locomotory behavior / dendritic shaft / learning / locomotory behavior / response to cocaine / negative regulation of insulin secretion / cellular response to nerve growth factor stimulus / visual learning / GABA-ergic synapse / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / cytoplasmic side of plasma membrane / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / terminal bouton / 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 / 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 / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling 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: 2.88 Å | |||||||||
![]() | Krumm BE / DiBerto JF / Olsen RHJ / Kang H / Slocum ST / Zhang S / Strachan RT / Fay JF / Roth BL | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator. 著者: Brian E Krumm / Jeffrey F DiBerto / Reid H J Olsen / Hye Jin Kang / Samuel T Slocum / Shicheng Zhang / Ryan T Strachan / Xi-Ping Huang / Lauren M Slosky / Anthony B Pinkerton / Lawrence S ...著者: Brian E Krumm / Jeffrey F DiBerto / Reid H J Olsen / Hye Jin Kang / Samuel T Slocum / Shicheng Zhang / Ryan T Strachan / Xi-Ping Huang / Lauren M Slosky / Anthony B Pinkerton / Lawrence S Barak / Marc G Caron / Terry Kenakin / Jonathan F Fay / Bryan L Roth / ![]() 要旨: The NTSR1 neurotensin receptor (NTSR1) is a G protein-coupled receptor (GPCR) found in the brain and peripheral tissues with neurotensin (NTS) being its endogenous peptide ligand. In the brain, NTS ...The NTSR1 neurotensin receptor (NTSR1) is a G protein-coupled receptor (GPCR) found in the brain and peripheral tissues with neurotensin (NTS) being its endogenous peptide ligand. In the brain, NTS modulates dopamine neuronal activity, induces opioid-independent analgesia, and regulates food intake. Recent studies indicate that biasing NTSR1 toward β-arrestin signaling can attenuate the actions of psychostimulants and other drugs of abuse. Here, we provide the cryoEM structures of NTSR1 ternary complexes with heterotrimeric Gq and GoA with and without the brain-penetrant small-molecule SBI-553. In functional studies, we discovered that SBI-553 displays complex allosteric actions exemplified by negative allosteric modulation for G proteins that are Gα subunit selective and positive allosteric modulation and agonism for β-arrestin translocation at NTSR1. Detailed structural analysis of the allosteric binding site illuminated the structural determinants for biased allosteric modulation of SBI-553 on NTSR1. | |||||||||
履歴 |
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構造の表示
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マップデータ | ![]() | 55 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 20.9 KB 20.9 KB | 表示 表示 | ![]() |
画像 | ![]() | 24.7 KB | ||
Filedesc metadata | ![]() | 6.8 KB | ||
その他 | ![]() ![]() | 59.4 MB 59.4 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-検証レポート
文書・要旨 | ![]() | 703 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 702.6 KB | 表示 | |
XML形式データ | ![]() | 12.2 KB | 表示 | |
CIF形式データ | ![]() | 14.3 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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注釈 | CryoEM structure of Go-coupled NTSR1 | ||||||||||||||||||||||||||||||||||||
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: 0.88 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: Half Map 1
ファイル | emd_29303_half_map_1.map | ||||||||||||
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注釈 | Half Map 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: Half Map 2
ファイル | emd_29303_half_map_2.map | ||||||||||||
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注釈 | Half Map 2 | ||||||||||||
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 : Ternary complex of NTSR1 MiniGo heterotrimer with scFv16
全体 | 名称: Ternary complex of NTSR1 MiniGo heterotrimer with scFv16 |
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要素 |
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-超分子 #1: Ternary complex of NTSR1 MiniGo heterotrimer with scFv16
超分子 | 名称: Ternary complex of NTSR1 MiniGo heterotrimer with scFv16 タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: all |
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由来(天然) | 生物種: ![]() ![]() |
分子量 | 理論値: 147 KDa |
-分子 #1: Neurotensin/neuromedin N
分子 | 名称: Neurotensin/neuromedin N / 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: 819.007 Da |
配列 | 文字列: RRPYIL UniProtKB: Neurotensin/neuromedin N |
-分子 #2: Neurotensin receptor type 1
分子 | 名称: Neurotensin receptor type 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: ![]() ![]() |
分子量 | 理論値: 45.842098 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MHHHHHHHHH HSDLEVLFQG PLGSGATSES DTAGPNSDLD VNTDIYSKVL VTAIYLALFV VGTVGNSVTL FTLARKKSLQ SLQSTVHYH LGSLALSDLL ILLLAMPVEL YNFIWVHHPW AFGDAGCRGY YFLRDACTYA TALNVASLSV ERYLAICHPF K AKTLMSRS ...文字列: MHHHHHHHHH HSDLEVLFQG PLGSGATSES DTAGPNSDLD VNTDIYSKVL VTAIYLALFV VGTVGNSVTL FTLARKKSLQ SLQSTVHYH LGSLALSDLL ILLLAMPVEL YNFIWVHHPW AFGDAGCRGY YFLRDACTYA TALNVASLSV ERYLAICHPF K AKTLMSRS RTKKFISAIW LASALLAIPM LFTMGLQNRS ADGTHPGGLV CTPIVDTATV KVVIQVNTFM SFLFPMLVIS IL NTVIANK LTVMVHQAAE QGRVCTVGTH NGLEHSTFNM TIEPGRVQAL RHGVLVLRAV VIAFVVCWLP YHVRRLMFCY ISD EQWTTF LFDFYHYFYM LTNALFYASS AINPILYNLV SANFRQVFLS TLACLCPGWR HRRKKRPTFS RKPNSMSSNH AFST SATRE TLY UniProtKB: Neurotensin receptor type 1 |
-分子 #3: Guanine nucleotide-binding protein G(o) subunit alpha
分子 | 名称: Guanine nucleotide-binding protein G(o) subunit alpha 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: 25.451166 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MGCTLSAEDK AAVERSKMIE KNLKEDGISA AKDVKLLLLG ADNSGKSTIV KQMKIIHGGS GGSGGTTGIV ETHFTFKNLH FRLFDVGGQ RSERKKWIHC FEDVTAIIFC VDLSDYNRMH ESLMLFDSIC NNKFFIDTSI ILFLNKKDLF GEKIKKSPLT I CFPEYTGP ...文字列: MGCTLSAEDK AAVERSKMIE KNLKEDGISA AKDVKLLLLG ADNSGKSTIV KQMKIIHGGS GGSGGTTGIV ETHFTFKNLH FRLFDVGGQ RSERKKWIHC FEDVTAIIFC VDLSDYNRMH ESLMLFDSIC NNKFFIDTSI ILFLNKKDLF GEKIKKSPLT I CFPEYTGP NTYEDAAAYI QAQFESKNRS PNKEIYCHMT CATDTNNAQV IFDAVTDIII ANNLRGCGLY UniProtKB: Guanine nucleotide-binding protein G(o) subunit alpha, Guanine nucleotide-binding protein G(o) subunit alpha |
-分子 #4: 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: 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: 39.418086 KDa |
組換発現 | 生物種: ![]() ![]() |
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 #5: 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: 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: 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 #6: scFv16
分子 | 名称: scFv16 / タイプ: protein_or_peptide / ID: 6 / 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: 28.668922 KDa |
組換発現 | 生物種: ![]() ![]() |
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 |
-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 / 詳細: 20mM Hepes, 0.1M NaCl, 0.00075% LMNG, 0.00075% GDN |
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グリッド | モデル: Quantifoil / 材質: GOLD / メッシュ: 300 / 前処理 - タイプ: GLOW DISCHARGE |
凍結 | 凍結剤: ETHANE-PROPANE |
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電子顕微鏡法
顕微鏡 | FEI TALOS ARCTICA |
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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: 44.0 e/Å2 |
電子線 | 加速電圧: 200 kV / 電子線源: ![]() |
電子光学系 | 照射モード: OTHER / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 3.2 µm / 最小 デフォーカス(公称値): 0.1 µm |
実験機器 | ![]() モデル: Talos Arctica / 画像提供: FEI Company |
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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: 2.88 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 560249 |
初期 角度割当 | タイプ: MAXIMUM LIKELIHOOD |
最終 角度割当 | タイプ: MAXIMUM LIKELIHOOD |