+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8j6r | ||||||
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タイトル | Cryo-EM structure of the MK-6892-bound human HCAR2-Gi1 complex | ||||||
要素 |
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キーワード | MEMBRANE PROTEIN (膜タンパク質) / hydroxycarboxylic acid receptor / MK-6892 / Class A GPCR | ||||||
機能・相同性 | 機能・相同性情報 nicotinic acid receptor activity / Hydroxycarboxylic acid-binding receptors / neutrophil apoptotic process / Class A/1 (Rhodopsin-like receptors) / positive regulation of neutrophil apoptotic process / positive regulation of adiponectin secretion / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding ...nicotinic acid receptor activity / Hydroxycarboxylic acid-binding receptors / neutrophil apoptotic process / Class A/1 (Rhodopsin-like receptors) / positive regulation of neutrophil apoptotic process / positive regulation of adiponectin secretion / 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 / negative regulation of lipid catabolic process / 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 / Olfactory Signaling Pathway / G-protein beta/gamma-subunit complex binding / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / 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 / 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 / response to peptide hormone / 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 / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / 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) / retina development in camera-type eye / 細胞結合 / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / 細胞皮質 / 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 / 細胞周期 / G protein-coupled receptor signaling pathway / lysosomal membrane / 細胞分裂 / GTPase activity / 中心体 / シナプス / protein-containing complex binding / 核小体 / GTP binding / magnesium ion binding / シグナル伝達 / extracellular exosome / 核質 / 生体膜 / 細胞膜 / 細胞質基質 / 細胞質 類似検索 - 分子機能 | ||||||
生物種 | Homo sapiens (ヒト) synthetic construct (人工物) | ||||||
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: 2.76 Å | ||||||
データ登録者 | Mao, C. / Gao, M. / Zang, S. / Zhu, Y. / Ma, X. / Zhang, Y. | ||||||
資金援助 | 1件
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引用 | ジャーナル: Nat Commun / 年: 2023 タイトル: Orthosteric and allosteric modulation of human HCAR2 signaling complex. 著者: Chunyou Mao / Mengru Gao / Shao-Kun Zang / Yanqing Zhu / Dan-Dan Shen / Li-Nan Chen / Liu Yang / Zhiwei Wang / Huibing Zhang / Wei-Wei Wang / Qingya Shen / Yanhui Lu / Xin Ma / Yan Zhang / 要旨: Hydroxycarboxylic acids are crucial metabolic intermediates involved in various physiological and pathological processes, some of which are recognized by specific hydroxycarboxylic acid receptors ...Hydroxycarboxylic acids are crucial metabolic intermediates involved in various physiological and pathological processes, some of which are recognized by specific hydroxycarboxylic acid receptors (HCARs). HCAR2 is one such receptor, activated by endogenous β-hydroxybutyrate (3-HB) and butyrate, and is the target for Niacin. Interest in HCAR2 has been driven by its potential as a therapeutic target in cardiovascular and neuroinflammatory diseases. However, the limited understanding of how ligands bind to this receptor has hindered the development of alternative drugs able to avoid the common flushing side-effects associated with Niacin therapy. Here, we present three high-resolution structures of HCAR2-Gi1 complexes bound to four different ligands, one potent synthetic agonist (MK-6892) bound alone, and the two structures bound to the allosteric agonist compound 9n in conjunction with either the endogenous ligand 3-HB or niacin. These structures coupled with our functional and computational analyses further our understanding of ligand recognition, allosteric modulation, and activation of HCAR2 and pave the way for the development of high-efficiency drugs with reduced side-effects. | ||||||
履歴 |
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-構造の表示
構造ビューア | 分子: MolmilJmol/JSmol |
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-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 8j6r.cif.gz | 217.8 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb8j6r.ent.gz | 168.2 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8j6r.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
その他 | その他のダウンロード |
-検証レポート
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/j6/8j6r ftp://data.pdbj.org/pub/pdb/validation_reports/j6/8j6r | HTTPS FTP |
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-関連構造データ
関連構造データ | 36012MC 8j6pC 8j6qC M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 (文献) |
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類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-リンク
-集合体
登録構造単位 |
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1 |
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-要素
-Guanine nucleotide-binding protein ... , 3種, 3分子 ABG
#1: タンパク質 | 分子量: 40225.801 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GNAI1 / Cell (発現宿主): Sf9 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P63096 |
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#2: タンパク質 | 分子量: 37285.734 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GNB1 / Cell (発現宿主): Sf9 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P62873 |
#3: 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) Homo sapiens (ヒト) / 遺伝子: GNG2 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P59768 |
-抗体 / タンパク質 / 糖 , 3種, 3分子 SR
#4: 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) synthetic construct (人工物) / Cell (発現宿主): Hi5 / 発現宿主: Trichoplusia ni (イラクサキンウワバ) |
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#5: タンパク質 | 分子量: 34366.074 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: HCAR2, GPR109A, HCA2, HM74A, NIACR1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: Q8TDS4 |
#7: 糖 | ChemComp-NAG / |
-非ポリマー , 2種, 2分子
#6: 化合物 | ChemComp-FI7 / |
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#8: 水 | ChemComp-HOH / |
-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 |
-試料調製
構成要素 | 名称: Cryo-EM structure of the MK-6892-bound human HCAR2-Gi1 complex タイプ: COMPLEX / Entity ID: #1-#5 / 由来: RECOMBINANT |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
由来(組換発現) | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
緩衝液 | pH: 7.5 |
試料 | 濃度: 15 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 |
-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: FIELD EMISSION GUN / 加速電圧: 300 kV / 照射モード: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELDBright-field microscopy / 最大 デフォーカス(公称値): 2000 nm / 最小 デフォーカス(公称値): 1000 nm / Cs: 2.7 mm |
試料ホルダ | 凍結剤: NITROGEN 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER |
撮影 | 電子線照射量: 40 e/Å2 フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) |
-解析
ソフトウェア | 名称: PHENIX / バージョン: 1.19.2_4158: / 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: 2.76 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 413723 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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