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基本情報
登録情報 | データベース: PDB / ID: 8hqm | |||||||||
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タイトル | Activation mechanism of GPR132 by NPGLY | |||||||||
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![]() | MEMBRANE PROTEIN / GPCR / GPR132 | |||||||||
機能・相同性 | ![]() negative regulation of G2/M transition of mitotic cell cycle / Class A/1 (Rhodopsin-like receptors) / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway ...negative regulation of G2/M transition of mitotic cell cycle / Class A/1 (Rhodopsin-like receptors) / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / 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 / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / 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 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / G1/S transition of mitotic cell cycle / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / 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 / phospholipase C-activating G protein-coupled receptor signaling pathway / cell cortex / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / 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 / cell division / lysosomal membrane / GTPase activity / centrosome / synapse / heme binding / protein-containing complex binding / nucleolus / GTP binding / magnesium ion binding / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytosol / cytoplasm 類似検索 - 分子機能 | |||||||||
生物種 | ![]() ![]() ![]() ![]() ![]() | |||||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.95 Å | |||||||||
![]() | Wang, J.L. / Ding, J.H. / Sun, J.P. / Yu, X. | |||||||||
資金援助 | ![]()
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![]() | ![]() 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. | |||||||||
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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PDBx/mmCIF形式 | ![]() | 236.1 KB | 表示 | ![]() |
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PDB形式 | ![]() | 178.7 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
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-関連構造データ
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リンク
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集合体
登録構造単位 | ![]()
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要素
-Guanine nucleotide-binding protein ... , 3種, 3分子 BCA
#1: タンパク質 | 分子量: 39489.160 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() 参照: UniProt: P62873 |
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#2: タンパク質 | 分子量: 6375.332 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() 参照: UniProt: P59768 |
#5: タンパク質 | 分子量: 40445.059 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() 参照: UniProt: P63096 |
-抗体 / タンパク質 / 非ポリマー , 3種, 3分子 HR![](data/chem/img/140.gif)
![](data/chem/img/140.gif)
#3: 抗体 | 分子量: 26610.615 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() 発現宿主: ![]() |
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#4: タンパク質 | 分子量: 57125.316 Da / 分子数: 1 / 由来タイプ: 組換発現 由来: (組換発現) ![]() ![]() ![]() 遺伝子: cybC, GPR132, G2A 発現宿主: ![]() 参照: UniProt: P0ABE7, UniProt: Q9UNW8 |
#6: 化合物 | ChemComp-140 / |
-詳細
研究の焦点であるリガンドがあるか | Y |
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-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
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試料調製
構成要素 | 名称: Cryo-EM structure of the NPGLY-GPR132-Gi complex / タイプ: COMPLEX / Entity ID: #1-#5 / 由来: MULTIPLE SOURCES |
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分子量 | 値: 160 kDa/nm / 実験値: YES |
由来(天然) | 生物種: ![]() |
由来(組換発現) | 生物種: ![]() |
緩衝液 | pH: 7.5 |
試料 | 濃度: 5 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
急速凍結 | 凍結剤: ETHANE |
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電子顕微鏡撮影
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TITAN KRIOS |
電子銃 | 電子線源: ![]() |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2500 nm / 最小 デフォーカス(公称値): 1000 nm |
撮影 | 電子線照射量: 60 e/Å2 フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) |
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解析
ソフトウェア | 名称: PHENIX / バージョン: 1.20.1_4487: / 分類: 精密化 |
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION |
3次元再構成 | 解像度: 2.95 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 444266 / 対称性のタイプ: POINT |