+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-34950 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
タイトル | Activation mechanism of GPR132 by NPGLY | |||||||||
マップデータ | ||||||||||
試料 |
| |||||||||
キーワード | GPCR / GPR132 / MEMBRANE PROTEIN | |||||||||
機能・相同性 | 機能・相同性情報 negative regulation of G2/M transition of mitotic cell cycle / Class A/1 (Rhodopsin-like receptors) / T cell migration / D2 dopamine receptor binding / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / G protein-coupled serotonin receptor binding / cellular response to forskolin / regulation of mitotic spindle organization ...negative regulation of G2/M transition of mitotic cell cycle / Class A/1 (Rhodopsin-like receptors) / T cell migration / D2 dopamine receptor binding / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / G protein-coupled serotonin receptor binding / cellular response to forskolin / regulation of mitotic spindle organization / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / electron transport chain / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / 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 / 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 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / response to peptide hormone / 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 / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / G1/S transition of mitotic cell cycle / ADP signalling through P2Y purinoceptor 1 / 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 / GDP binding / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / cell cortex / phospholipase C-activating G protein-coupled receptor signaling pathway / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) 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 / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / periplasmic space / electron transfer activity / iron ion binding / G protein-coupled receptor signaling pathway / lysosomal membrane / cell division / GTPase activity / centrosome / heme binding / synapse / protein-containing complex binding / GTP binding / nucleolus / magnesium ion binding / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytosol / cytoplasm 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) / Mus musculus (ハツカネズミ) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.95 Å | |||||||||
データ登録者 | Wang JL / Ding JH / Sun JP / Yu X | |||||||||
資金援助 | 中国, 2件
| |||||||||
引用 | ジャーナル: Nat Metab / 年: 2023 タイトル: Functional screening and rational design of compounds targeting GPR132 to treat diabetes. 著者: Jia-Le Wang / Xiao-Dong Dou / Jie Cheng / Ming-Xin Gao / Guo-Feng Xu / Wei Ding / Jin-Hui Ding / Yu Li / Si-Han Wang / Zhao-Wei Ji / Xin-Yi Zhao / Tong-Yu Huo / Cai-Fang Zhang / Ya-Meng Liu / ...著者: Jia-Le Wang / Xiao-Dong Dou / Jie Cheng / Ming-Xin Gao / Guo-Feng Xu / Wei Ding / Jin-Hui Ding / Yu Li / Si-Han Wang / Zhao-Wei Ji / Xin-Yi Zhao / Tong-Yu Huo / Cai-Fang Zhang / Ya-Meng Liu / Xue-Ying Sha / Jia-Rui Gao / Wen-Hui Zhang / Yong Hao / Cheng Zhang / Jin-Peng Sun / Ning Jiao / Xiao Yu / 要旨: Chronic inflammation due to islet-residing macrophages plays key roles in the development of type 2 diabetes mellitus. By systematically profiling intra-islet lipid-transmembrane receptor signalling ...Chronic inflammation due to islet-residing macrophages plays key roles in the development of type 2 diabetes mellitus. By systematically profiling intra-islet lipid-transmembrane receptor signalling in islet-resident macrophages, we identified endogenous 9(S)-hydroxy-10,12-octadecadienoic acid-G-protein-coupled receptor 132 (GPR132)-Gi signalling as a significant contributor to islet macrophage reprogramming and found that GPR132 deficiency in macrophages reversed metabolic disorders in mice fed a high-fat diet. The cryo-electron microscopy structures of GPR132 bound with two endogenous agonists, N-palmitoylglycine and 9(S)-hydroxy-10,12-octadecadienoic acid, enabled us to rationally design both GPR132 agonists and antagonists with high potency and selectivity through stepwise translational approaches. We ultimately identified a selective GPR132 antagonist, NOX-6-18, that modulates macrophage reprogramming within pancreatic islets, decreases weight gain and enhances glucose metabolism in mice fed a high-fat diet. Our study not only illustrates that intra-islet lipid signalling contributes to islet macrophage reprogramming but also provides a broadly applicable strategy for the identification of important G-protein-coupled receptor targets in pathophysiological processes, followed by the rational design of therapeutic leads for refractory diseases such as diabetes. | |||||||||
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 | emd_34950.map.gz | 11 MB | EMDBマップデータ形式 | |
---|---|---|---|---|
ヘッダ (付随情報) | emd-34950-v30.xml emd-34950.xml | 20.5 KB 20.5 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_34950.png | 104.7 KB | ||
Filedesc metadata | emd-34950.cif.gz | 6.8 KB | ||
その他 | emd_34950_half_map_1.map.gz emd_34950_half_map_2.map.gz | 20.6 MB 20.6 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-34950 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-34950 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_34950_validation.pdf.gz | 717.9 KB | 表示 | EMDB検証レポート |
---|---|---|---|---|
文書・詳細版 | emd_34950_full_validation.pdf.gz | 717.5 KB | 表示 | |
XML形式データ | emd_34950_validation.xml.gz | 10.3 KB | 表示 | |
CIF形式データ | emd_34950_validation.cif.gz | 12 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-34950 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-34950 | HTTPS FTP |
-関連構造データ
-リンク
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
---|---|
「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_34950.map.gz / 形式: CCP4 / 大きさ: 22.2 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
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: 1.04 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_34950_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_34950_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 : Cryo-EM structure of the NPGLY-GPR132-Gi complex
全体 | 名称: Cryo-EM structure of the NPGLY-GPR132-Gi complex |
---|---|
要素 |
|
-超分子 #1: Cryo-EM structure of the NPGLY-GPR132-Gi complex
超分子 | 名称: Cryo-EM structure of the NPGLY-GPR132-Gi complex / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#5 |
---|---|
由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 160 kDa/nm |
-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: Homo sapiens (ヒト) |
分子量 | 理論値: 39.48916 KDa |
組換発現 | 生物種: Baculovirus expression vector pFastBac1-HM (ウイルス) |
配列 | 文字列: MHHHHHHLEV LFQGPGSSQS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR ...文字列: MHHHHHHLEV LFQGPGSSQS 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 #2: 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: 2 / コピー数: 1 / 光学異性体: LEVO |
---|---|
由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 6.375332 KDa |
組換発現 | 生物種: Baculovirus expression vector pFastBac1-HM (ウイルス) |
配列 | 文字列: NTASIAQARK LVEQLKMEAN IDRIKVSKAA ADLMAYCEAH AKEDPLLTPV PASENPFR UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-分子 #3: scFv16
分子 | 名称: scFv16 / 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: Mus musculus (ハツカネズミ) |
分子量 | 理論値: 26.610615 KDa |
組換発現 | 生物種: Baculovirus expression vector pFastBac1-HM (ウイルス) |
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 KGS |
-分子 #4: Soluble cytochrome b562,Probable G-protein coupled receptor 132
分子 | 名称: Soluble cytochrome b562,Probable G-protein coupled receptor 132 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: Homo sapiens (ヒト) |
分子量 | 理論値: 57.125316 KDa |
組換発現 | 生物種: Baculovirus expression vector pFastBac1-HM (ウイルス) |
配列 | 文字列: MKTIIALSYI FCLVFADYKD DDDKADLEDN WETLNDNLKV IEKADNAAQV KDALTKMRAA ALDAQKATPP KLEDKSPDSP EMKDFRHGF DILVGQIDDA LKLANEGKVK EAQAAAEQLK TTRNAYIQKY LMCPMLLKNG YNGNATPVTT TAPWASLGLS A KTCNNVSF ...文字列: MKTIIALSYI FCLVFADYKD DDDKADLEDN WETLNDNLKV IEKADNAAQV KDALTKMRAA ALDAQKATPP KLEDKSPDSP EMKDFRHGF DILVGQIDDA LKLANEGKVK EAQAAAEQLK TTRNAYIQKY LMCPMLLKNG YNGNATPVTT TAPWASLGLS A KTCNNVSF EESRIVLVVV YSAVCTLGVP ANCLTAWLAL LQVLQGNVLA VYLLCLALCE LLYTGTLPLW VIYIRNQHRW TL GLLACKV TAYIFFCNIY VSILFLCCIS CDRFVAVVYA LESRGRRRRR TAILISACIF ILVGIVHYPV FQTEDKETCF DML QMDSRI AGYYYARFTV GFAIPLSIIA FTNHRIFRSI KQSMGLSAAQ KAKVKHSAIA VVVIFLVCFA PYHLVLLVKA AAFS YYRGD RNAMCGLEER LYTASVVFLC LSTVNGVADP IIYVLATDHS RQEVSRIHKG WKEWSMKTDV TRLTHSRDTE ELQSP VALA DHYTFSRPVH PPGSPCPAKR LIEESC UniProtKB: Soluble cytochrome b562, Probable G-protein coupled receptor 132 |
-分子 #5: 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: 5 / コピー数: 1 / 光学異性体: LEVO |
---|---|
由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 40.445059 KDa |
組換発現 | 生物種: Baculovirus expression vector pFastBac1-HM (ウイルス) |
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 FDVGAQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCS TDTKNVQFVF DAVTDVIIKN NLKDCGLF UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1 |
-分子 #6: N-PALMITOYLGLYCINE
分子 | 名称: N-PALMITOYLGLYCINE / タイプ: ligand / ID: 6 / コピー数: 1 / 式: 140 |
---|---|
分子量 | 理論値: 313.475 Da |
Chemical component information | ChemComp-140: |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
---|---|
解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
濃度 | 5 mg/mL |
---|---|
緩衝液 | pH: 7.5 |
凍結 | 凍結剤: ETHANE |
-電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
---|---|
撮影 | フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) 平均電子線量: 60.0 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: SPOT SCAN / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2.5 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: |
---|---|
最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 2.95 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 444266 |
初期 角度割当 | タイプ: ANGULAR RECONSTITUTION |
最終 角度割当 | タイプ: ANGULAR RECONSTITUTION |