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基本情報
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タイトル | CryoEM structure of Gq coupled MRGPRX4 with agonist DCA-3P | |||||||||
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![]() | MRGPRX4 / Bile acid / Cholestatic itch / GPCR / Agonist / MEMBRANE PROTEIN | |||||||||
機能・相同性 | ![]() bioluminescence / generation of precursor metabolites and energy / electron transport chain / G protein-coupled receptor activity / 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 ...bioluminescence / generation of precursor metabolites and energy / electron transport chain / G protein-coupled receptor activity / 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 / 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 / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / 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 / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Ras protein signal transduction / periplasmic space / Extra-nuclear estrogen signaling / electron transfer activity / cell population proliferation / G protein-coupled receptor signaling pathway / iron ion binding / lysosomal membrane / GTPase activity / synapse / heme binding / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm 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: 2.9 Å | |||||||||
![]() | Yang J / Fan JP / Lei XG | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structure-guided discovery of bile acid derivatives for treating liver diseases without causing itch. 著者: Jun Yang / Tianjun Zhao / Junping Fan / Huaibin Zou / Guangyi Lan / Fusheng Guo / Yaocheng Shi / Han Ke / Huasheng Yu / Zongwei Yue / Xin Wang / Yingjie Bai / Shuai Li / Yingjun Liu / ...著者: Jun Yang / Tianjun Zhao / Junping Fan / Huaibin Zou / Guangyi Lan / Fusheng Guo / Yaocheng Shi / Han Ke / Huasheng Yu / Zongwei Yue / Xin Wang / Yingjie Bai / Shuai Li / Yingjun Liu / Xiaoming Wang / Yu Chen / Yulong Li / Xiaoguang Lei / ![]() ![]() 要旨: Chronic itch is a debilitating symptom profoundly impacting the quality of life in patients with liver diseases like cholestasis. Activation of the human G-protein coupled receptor, MRGPRX4 (hX4), by ...Chronic itch is a debilitating symptom profoundly impacting the quality of life in patients with liver diseases like cholestasis. Activation of the human G-protein coupled receptor, MRGPRX4 (hX4), by bile acids (BAs) is implicated in promoting cholestasis itch. However, the detailed underlying mechanisms remain elusive. Here, we identified 3-sulfated BAs that are elevated in cholestatic patients with itch symptoms. We solved the cryo-EM structure of hX4-Gq in a complex with 3-phosphated deoxycholic acid (DCA-3P), a mimic of the endogenous 3-sulfated deoxycholic acid (DCA-3S). This structure revealed an unprecedented ligand-binding pocket in MRGPR family proteins, highlighting the crucial role of the 3-hydroxyl (3-OH) group on BAs in activating hX4. Guided by this structural information, we designed and developed compound 7 (C7), a BA derivative lacking the 3-OH. Notably, C7 effectively alleviates hepatic injury and fibrosis in liver disease models while significantly mitigating the itch side effects. | |||||||||
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 | ![]() | 59.7 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 20.1 KB 20.1 KB | 表示 表示 | ![]() |
画像 | ![]() | 24.6 KB | ||
Filedesc metadata | ![]() | 7.1 KB | ||
その他 | ![]() ![]() | 59.3 MB 59.3 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 8k4sMC ![]() 8kexC 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 ![]() |
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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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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 |
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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: #2
ファイル | emd_36890_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: #1
ファイル | emd_36890_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 : Complex of MRGPRX4 with Gq and agonist DCA-3P
全体 | 名称: Complex of MRGPRX4 with Gq and agonist DCA-3P |
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要素 |
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-超分子 #1: Complex of MRGPRX4 with Gq and agonist DCA-3P
超分子 | 名称: Complex of MRGPRX4 with Gq and agonist DCA-3P / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #2-#5, #1 |
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由来(天然) | 生物種: ![]() |
-分子 #1: Soluble cytochrome b562,Mas-related G-protein coupled receptor me...
分子 | 名称: Soluble cytochrome b562,Mas-related G-protein coupled receptor member X4,Green fluorescent protein タイプ: protein_or_peptide / ID: 1 詳細: The domain (1-8) is corresponding to Flag-tag. The doamin (9-116) is corresponding to Soluble cytochrome b562. The domain (117-438) is corresponding to MRGPRX4 (GenBank: AY042216.1). The ...詳細: The domain (1-8) is corresponding to Flag-tag. The doamin (9-116) is corresponding to Soluble cytochrome b562. The domain (117-438) is corresponding to MRGPRX4 (GenBank: AY042216.1). The domain (439-710) is corresponding to HRV 3C site and GFP. 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: 79.79568 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: DYKDDDDKEF ADLEDNWETL NDNLKVIEKA DNAAQVKDAL TKMRAAALDA QKATPPKLED KSPDSPEMKD FRHGFDILVG QIDDALKLA NEGKVKEAQA AAEQLKTTRN AYIQKYLMDP TVPVFGTKLT PINGREETPC YNQTLSFTVL TCIISLVGLT G NAVVLWLL ...文字列: DYKDDDDKEF ADLEDNWETL NDNLKVIEKA DNAAQVKDAL TKMRAAALDA QKATPPKLED KSPDSPEMKD FRHGFDILVG QIDDALKLA NEGKVKEAQA AAEQLKTTRN AYIQKYLMDP TVPVFGTKLT PINGREETPC YNQTLSFTVL TCIISLVGLT G NAVVLWLL GYRMRRNAVS IYILNLAAAD FLFLSFQIIR LPLRLINISH LIRKILVSVM TFPYFTGLSM LSAISTERCL SV LWPIWYR CRRPTHLSAV VCVLLWGLSL LFSMLEWRFC DFLFSGADSS WCETSDFIPV AWLIFLCVVL CVSSLVLLVR ILC GSRKMP LTRLYVTILL TVLVFLLCGL PFGILGALIY RMHLNLEVLY CHVYLVCMSL SSLNSSANPI IYFFVGSFRQ RQNR QNLKL VLQRALQDKP EVDKGEGQLP EESLELSGSR LGPLELEVLF QGPSKGEELF TGVVPILVEL DGDVNGHKFS VRGEG EGDA TNGKLTLKFI CTTGKLPVPW PTLVTTLTYG VQCFSRYPDH MKRHDFFKSA MPEGYVQERT ISFKDDGTYK TRAEVK FEG DTLVNRIELK GIDFKEDGNI LGHKLEYNFN SHNVYITADK QKNGIKANFK IRHNVEDGSV QLADHYQQNT PIGDGPV LL PDNHYLSTQS VLSKDPNEKR DHMVLLEFVT AAGITHGMDE WSHPQFEKGG GSGGGSGGSA WSHPQFEK UniProtKB: Soluble cytochrome b562, Mas-related G-protein coupled receptor member X4, Green fluorescent protein |
-分子 #2: Gs-mini-Gq chimera
分子 | 名称: Gs-mini-Gq chimera / 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: 28.084832 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA ...文字列: MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA RYTTPEDATP EPGEDPRVTR AKYFIRKEFV DISTASGDGR HICYPHFTCA VDTENARRIF NDCKDIILQM NL REYNLV |
-分子 #3: 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: 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: 37.342785 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...文字列: GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD INAICFFPNG NA FATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGV TDDGMA VATGSWDSFL KIWN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-分子 #4: 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: 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: 8.506765 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI LGSAGSAGSA UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-分子 #5: scFv16
分子 | 名称: scFv16 / タイプ: protein_or_peptide / ID: 5 詳細: Author stated: the domain (3-254) is corresponding to this scFv16 (1-252 amino acids). 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: 26.955045 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: GSMDVQLVES GGGLVQPGGS RKLSCSASGF AFSSFGMHWV RQAPEKGLEW VAYISSGSGT IYYADTVKGR FTISRDDPKN TLFLQMTSL RSEDTAMYYC VRSIYYYGSS PFDFWGQGTT LTVSSGGGGS GGGGSGGGGS DIVMTQATSS VPVTPGESVS I SCRSSKSL ...文字列: GSMDVQLVES GGGLVQPGGS RKLSCSASGF AFSSFGMHWV RQAPEKGLEW VAYISSGSGT IYYADTVKGR FTISRDDPKN TLFLQMTSL RSEDTAMYYC VRSIYYYGSS PFDFWGQGTT LTVSSGGGGS GGGGSGGGGS DIVMTQATSS VPVTPGESVS I SCRSSKSL LHSNGNTYLY WFLQRPGQSP QLLIYRMSNL ASGVPDRFSG SGSGTAFTLT ISRLEAEDVG VYYCMQHLEY PL TFGAGTK LELKAAA |
-分子 #6: (4~{R})-4-[(3~{R},5~{R},8~{R},9~{S},10~{S},12~{S},13~{R},14~{S},1...
分子 | 名称: (4~{R})-4-[(3~{R},5~{R},8~{R},9~{S},10~{S},12~{S},13~{R},14~{S},17~{R})-10,13-dimethyl-12-oxidanyl-3-phosphonooxy-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1~{H}-cyclopenta[a] ...名称: (4~{R})-4-[(3~{R},5~{R},8~{R},9~{S},10~{S},12~{S},13~{R},14~{S},17~{R})-10,13-dimethyl-12-oxidanyl-3-phosphonooxy-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1~{H}-cyclopenta[a]phenanthren-17-yl]pentanoic acid タイプ: ligand / ID: 6 / コピー数: 1 / 式: JW0 |
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分子量 | 理論値: 472.552 Da |
-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: 7.4 |
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凍結 | 凍結剤: ETHANE |
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電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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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: ![]() |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2.2 µm / 最小 デフォーカス(公称値): 1.1 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: 2.9 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 451859 |
初期 角度割当 | タイプ: RANDOM ASSIGNMENT |
最終 角度割当 | タイプ: MAXIMUM LIKELIHOOD |