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データを開く
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基本情報
| 登録情報 | ![]() | |||||||||
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| タイトル | Biased agonist bound CB1-Gi structure | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | G Protein-coupled receptor (GPCR) / G protein / Gi / biased ligand / SIGNALING PROTEIN | |||||||||
| 機能・相同性 | 機能・相同性情報cannabinoid signaling pathway / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / regulation of presynaptic cytosolic calcium ion concentration / Class A/1 (Rhodopsin-like receptors) / axonal fasciculation / regulation of metabolic process / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex ...cannabinoid signaling pathway / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / regulation of presynaptic cytosolic calcium ion concentration / Class A/1 (Rhodopsin-like receptors) / axonal fasciculation / regulation of metabolic process / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / Adenylate cyclase inhibitory pathway / T cell migration / D2 dopamine receptor binding / response to prostaglandin E / adenylate cyclase regulator activity / G protein-coupled serotonin receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / cellular response to forskolin / regulation of mitotic spindle organization / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / response to peptide hormone / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / GABA-ergic synapse / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / centriolar satellite / 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 / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / 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 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / GDP binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / glucose homeostasis / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / actin cytoskeleton / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / G protein activity / presynaptic membrane / growth cone / GTPase binding / Ca2+ pathway / fibroblast proliferation / midbody / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / cell cortex / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / 加水分解酵素; 酸無水物に作用; GTPに作用・細胞または細胞小器官の運動に関与 / Ras protein signal transduction / mitochondrial outer membrane / Extra-nuclear estrogen signaling / cell population proliferation / ciliary basal body / G protein-coupled receptor signaling pathway / membrane raft / lysosomal membrane / cell division / GTPase activity / synapse / centrosome / GTP binding 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: 3.03 Å | |||||||||
データ登録者 | Rangari VA / O'Brien ES / Kobilka BK / Krishna Kumar K / Majumdar S | |||||||||
| 資金援助 | 米国, 1件
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引用 | ジャーナル: Nature / 年: 2025タイトル: A cryptic pocket in CB1 drives peripheral and functional selectivity. 著者: Vipin Ashok Rangari / Evan S O'Brien / Alexander S Powers / Richard A Slivicki / Zachariah Bertels / Kevin Appourchaux / Deniz Aydin / Nokomis Ramos-Gonzalez / Juliet Mwirigi / Li Lin / ...著者: Vipin Ashok Rangari / Evan S O'Brien / Alexander S Powers / Richard A Slivicki / Zachariah Bertels / Kevin Appourchaux / Deniz Aydin / Nokomis Ramos-Gonzalez / Juliet Mwirigi / Li Lin / Elizaveta Mangutov / Briana L Sobecks / Yaseen Awad-Agbaria / Manoj B Uphade / Jhoan Aguilar / Teja Nikhil Peddada / Yuki Shiimura / Xi-Ping Huang / Jakayla Folarin-Hines / Maria Payne / Anirudh Kalathil / Balazs R Varga / Brian K Kobilka / Amynah A Pradhan / Michael D Cameron / Kaavya Krishna Kumar / Ron O Dror / Robert W Gereau / Susruta Majumdar / ![]() 要旨: The current opioid overdose epidemic highlights the urgent need to develop safer and more effective treatments for chronic pain. Cannabinoid receptor type 1 (CB1) is a promising non-opioid target for ...The current opioid overdose epidemic highlights the urgent need to develop safer and more effective treatments for chronic pain. Cannabinoid receptor type 1 (CB1) is a promising non-opioid target for pain relief, but its clinical use has been limited by centrally mediated psychoactivity and tolerance. We overcame both issues by designing peripherally restricted CB1 agonists that minimize arrestin recruitment. We achieved these goals by computationally designing positively charged derivatives of the potent CB1 agonist MDMB-Fubinaca. We designed these ligands to occupy a cryptic pocket identified through molecular dynamics simulations-an extended binding pocket that opens rarely and leads to the conserved signalling residue D (ref. ). We used structure determination, pharmacological assays and molecular dynamics simulations to verify the binding modes of these ligands and to determine the molecular mechanism by which they achieve this dampening of arrestin recruitment. Our lead ligand, VIP36, is highly peripherally restricted and demonstrates notable efficacy in three mouse pain models, with 100-fold dose separation between analgesic efficacy and centrally mediated side effects. VIP36 exerts analgesic efficacy through peripheral CB1 receptors and shows limited analgesic tolerance. These results show how targeting a cryptic pocket in a G-protein-coupled receptor can lead to enhanced peripheral selectivity, biased signalling, desired in vivo pharmacology and reduced adverse effects. This has substantial implications for chronic pain treatment but could also revolutionize the design of drugs targeting other G-protein-coupled receptors. | |||||||||
| 履歴 |
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構造の表示
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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_44247.map.gz | 9.8 MB | EMDBマップデータ形式 | |
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| ヘッダ (付随情報) | emd-44247-v30.xml emd-44247.xml | 23.5 KB 23.5 KB | 表示 表示 | EMDBヘッダ |
| 画像 | emd_44247.png | 53.9 KB | ||
| Filedesc metadata | emd-44247.cif.gz | 7.4 KB | ||
| その他 | emd_44247_half_map_1.map.gz emd_44247_half_map_2.map.gz | 98.6 MB 98.6 MB | ||
| アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-44247 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-44247 | HTTPS FTP |
-検証レポート
| 文書・要旨 | emd_44247_validation.pdf.gz | 768 KB | 表示 | EMDB検証レポート |
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| 文書・詳細版 | emd_44247_full_validation.pdf.gz | 767.6 KB | 表示 | |
| XML形式データ | emd_44247_validation.xml.gz | 13.8 KB | 表示 | |
| CIF形式データ | emd_44247_validation.cif.gz | 16.3 KB | 表示 | |
| アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-44247 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-44247 | HTTPS FTP |
-関連構造データ
| 関連構造データ | ![]() 9b65MC ![]() 9b54C 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 ( |
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| 類似構造データ | 類似検索 - 機能・相同性 F&H 検索 |
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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 |
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マップ
| ファイル | ダウンロード / ファイル: emd_44247.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: 0.92 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_44247_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_44247_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 : CB1-Gi complex
| 全体 | 名称: CB1-Gi complex |
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| 要素 |
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-超分子 #1: CB1-Gi complex
| 超分子 | 名称: CB1-Gi complex / 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 #1: Guanine nucleotide-binding protein G(i) subunit alpha-1
| 分子 | 名称: Guanine nucleotide-binding protein G(i) subunit alpha-1 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: 40.415031 KDa |
| 組換発現 | 生物種: Trichoplusia ni (イラクサキンウワバ) |
| 配列 | 文字列: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...文字列: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGGQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCA TDTKNVQFVF DAVTDVIIKN NLKDCGLF UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1 |
-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: 37.671102 KDa |
| 組換発現 | 生物種: Trichoplusia ni (イラクサキンウワバ) |
| 配列 | 文字列: PGSSGSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQD GKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY LSCCRFLDDN Q IVTSSGDT ...文字列: PGSSGSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQD GKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY LSCCRFLDDN Q IVTSSGDT TCALWDIETG QQTTTFTGHT GDVMSLSLAP DTRLFVSGAC DASAKLWDVR EGMCRQTFTG HESDINAICF FP NGNAFAT GSDDATCRLF DLRADQELMT YSHDNIICGI TSVSFSKSGR LLLAGYDDFN CNVWDALKAD RAGVLAGHDN RVS CLGVTD DGMAVATGSW DSFLKIWN 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: Trichoplusia ni (イラクサキンウワバ) |
| 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: Cannabinoid receptor 1
| 分子 | 名称: Cannabinoid receptor 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: Homo sapiens (ヒト) |
| 分子量 | 理論値: 55.678535 KDa |
| 組換発現 | 生物種: ![]() |
| 配列 | 文字列: DYKDDDDAMK SILDGLADTT FRTITTDLLY VGSNDIQYED IKGDMASKLG YFPQKFPLTS FRGSPFQEKM TAGDNPQLVP ADQVNITEF YNKSLSENLY FQGSFKENEE NIQCGENFMD IECFMVLNPS QQLAIAVLSL TLGTFTVLEN LLVLCVILHS R SLRCRPSY ...文字列: DYKDDDDAMK SILDGLADTT FRTITTDLLY VGSNDIQYED IKGDMASKLG YFPQKFPLTS FRGSPFQEKM TAGDNPQLVP ADQVNITEF YNKSLSENLY FQGSFKENEE NIQCGENFMD IECFMVLNPS QQLAIAVLSL TLGTFTVLEN LLVLCVILHS R SLRCRPSY HFIGSLAVAD LLGSVIFVYS FIDFHVFHRK DSRNVFLFKL GGVTASFTAS VGSLFLTAID RYISIHRPLA YK RIVTRPK AVVAFCLMWT IAIVIAVLPL LGWNCEKLQS VCSDIFPHID ETYLMFWIGV TSVLLLFIVY AYMYILWKAH SHA VRMIQR GTQKSIIIHT SEDGKVQVTR PDQARMDIRL AKTLVLILVV LIICWGPLLA IMVYDVFGKM NKLIKTVFAF CSML CLLNS TVNPIIYALR SKDLRHAFRS MFPSCEGTAQ PLDNSMGDSD CLHKHANNAA SVHRAAESCI KSTVKIAKVT MSVST DTSA EALGSHHHHH H UniProtKB: Cannabinoid receptor 1 |
-分子 #5: scFv16
| 分子 | 名称: scFv16 / 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: 27.784896 KDa |
| 組換発現 | 生物種: Trichoplusia ni (イラクサキンウワバ) |
| 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 KAAAHHHHHH HH |
-分子 #6: methyl N-{1-[(4-fluorophenyl)methyl]-1H-indazole-3-carbonyl}-3-me...
| 分子 | 名称: methyl N-{1-[(4-fluorophenyl)methyl]-1H-indazole-3-carbonyl}-3-methyl-L-valinate タイプ: ligand / ID: 6 / コピー数: 1 / 式: KCA |
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| 分子量 | 理論値: 397.443 Da |
| Chemical component information | ![]() ChemComp-KCA: |
-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 |
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試料調製
| 緩衝液 | pH: 7.5 |
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| 凍結 | 凍結剤: ETHANE |
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電子顕微鏡法
| 顕微鏡 | TFS KRIOS |
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| 撮影 | フィルム・検出器のモデル: FEI FALCON IV (4k x 4k) 平均電子線量: 58.0 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: DARK 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): 0.7000000000000001 µm |
| 実験機器 | ![]() モデル: Titan Krios / 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: 3.03 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 161137 |
| 初期 角度割当 | タイプ: RANDOM ASSIGNMENT |
| 最終 角度割当 | タイプ: MAXIMUM LIKELIHOOD |
-原子モデル構築 1
| 精密化 | 空間: REAL |
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| 得られたモデル | ![]() PDB-9b65: |
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コントローラー
万見について




キーワード
Homo sapiens (ヒト)
データ登録者
米国, 1件
引用































Z (Sec.)
Y (Row.)
X (Col.)




































Trichoplusia ni (イラクサキンウワバ)
FIELD EMISSION GUN

