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基本情報
登録情報 | ![]() | |||||||||
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タイトル | CryoEM Structure of HCA2-Gi1 in complex with MK-1903 | |||||||||
![]() | Structure of HCA2-Gi1 in complex with MK-1903 | |||||||||
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![]() | GPCR / HCA2 / MK 1903 / MEMBRANE PROTEIN | |||||||||
機能・相同性 | ![]() nicotinic acid receptor activity / Hydroxycarboxylic acid-binding receptors / neutrophil apoptotic process / positive regulation of neutrophil apoptotic process / Class A/1 (Rhodopsin-like receptors) / positive regulation of adiponectin secretion / negative regulation of lipid catabolic process / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration ...nicotinic acid receptor activity / Hydroxycarboxylic acid-binding receptors / neutrophil apoptotic process / positive regulation of neutrophil apoptotic process / Class A/1 (Rhodopsin-like receptors) / positive regulation of adiponectin secretion / negative regulation of lipid catabolic process / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration / Adenylate cyclase inhibitory pathway / 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 / response to peptide hormone / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / centriolar satellite / G-protein beta/gamma-subunit complex binding / 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 / GDP binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / cell junction / 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) / retina development in camera-type eye / G protein activity / GTPase binding / Ca2+ pathway / midbody / fibroblast proliferation / 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 / 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 / Extra-nuclear estrogen signaling / cell population proliferation / ciliary basal body / G protein-coupled receptor signaling pathway / lysosomal membrane / cell division / GTPase activity / synapse / centrosome / GTP binding / protein-containing complex binding / nucleolus / magnesium ion binding / Golgi apparatus / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane 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: 3.24 Å | |||||||||
![]() | Krumm BE / Kang HJ / Diberto JF / Kapolka NJ / Gumpper RH / Olsen RHJ / Huang XP / Zhang S / Fay JF / Roth BL | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structure-guided design of a peripherally restricted chemogenetic system. 著者: Hye Jin Kang / Brian E Krumm / Adrien Tassou / Matan Geron / Jeffrey F DiBerto / Nicholas J Kapolka / Ryan H Gumpper / Kensuke Sakamoto / D Dewran Kocak / Reid H J Olsen / Xi-Ping Huang / ...著者: Hye Jin Kang / Brian E Krumm / Adrien Tassou / Matan Geron / Jeffrey F DiBerto / Nicholas J Kapolka / Ryan H Gumpper / Kensuke Sakamoto / D Dewran Kocak / Reid H J Olsen / Xi-Ping Huang / Shicheng Zhang / Karen L Huang / Saheem A Zaidi / MyV T Nguyen / Min Jeong Jo / Vsevolod Katritch / Jonathan F Fay / Grégory Scherrer / Bryan L Roth / ![]() ![]() 要旨: Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remotely controlling cellular signaling, neural activity, behavior, and physiology. Using a structure- ...Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remotely controlling cellular signaling, neural activity, behavior, and physiology. Using a structure-guided approach, we provide a peripherally restricted Gi-DREADD, hydroxycarboxylic acid receptor DREADD (HCAD), whose native receptor is minimally expressed in the brain, and a chemical actuator that does not cross the blood-brain barrier (BBB). This was accomplished by combined mutagenesis, analoging via an ultra-large make-on-demand library, structural determination of the designed DREADD receptor via cryoelectron microscopy (cryo-EM), and validation of HCAD function. Expression and activation of HCAD in dorsal root ganglion (DRG) neurons inhibit action potential (AP) firing and reduce both acute and tissue-injury-induced inflammatory pain. The HCAD chemogenetic system expands the possibilities for studying numerous peripheral systems with little adverse effects on the central nervous system (CNS). The structure-guided approach used to generate HCAD also has the potential to accelerate the development of emerging chemogenetic tools for basic and translational sciences. | |||||||||
履歴 |
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構造の表示
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マップデータ | ![]() | 162.8 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 22.3 KB 22.3 KB | 表示 表示 | ![]() |
画像 | ![]() | 48 KB | ||
Filedesc metadata | ![]() | 7 KB | ||
その他 | ![]() ![]() | 159.6 MB 159.6 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-検証レポート
文書・要旨 | ![]() | 1.1 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.1 MB | 表示 | |
XML形式データ | ![]() | 14.8 KB | 表示 | |
CIF形式データ | ![]() | 17.5 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
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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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注釈 | Structure of HCA2-Gi1 in complex with MK-1903 | ||||||||||||||||||||||||||||||||||||
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: 0.8893 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: Half Map B
ファイル | emd_42538_half_map_1.map | ||||||||||||
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注釈 | Half Map B | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: Half Map A
ファイル | emd_42538_half_map_2.map | ||||||||||||
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注釈 | Half Map A | ||||||||||||
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 : Human HCA2-Gai1 in complex with MK1903
全体 | 名称: Human HCA2-Gai1 in complex with MK1903 |
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要素 |
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-超分子 #1: Human HCA2-Gai1 in complex with MK1903
超分子 | 名称: Human HCA2-Gai1 in complex with MK1903 / 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: ![]() |
-分子 #1: Hydroxycarboxylic acid receptor 2
分子 | 名称: Hydroxycarboxylic acid receptor 2 / 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: ![]() |
分子量 | 理論値: 42.297867 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: QGGTTMNRHH LQDHFLEIDK KNCCVFRDDF IVKVLPPVLG LEFIFGLLGN GLALWIFCFH LKSWKSSRIF LFNLAVADFL LIICLPFLM DNYVRRWDWK FGDIPCRLML FMLAMNRQGS IIFLTVVAVA RYFRVVHPHH ALNKISNRTA AIISCLLWGI T IGLTVHLL ...文字列: QGGTTMNRHH LQDHFLEIDK KNCCVFRDDF IVKVLPPVLG LEFIFGLLGN GLALWIFCFH LKSWKSSRIF LFNLAVADFL LIICLPFLM DNYVRRWDWK FGDIPCRLML FMLAMNRQGS IIFLTVVAVA RYFRVVHPHH ALNKISNRTA AIISCLLWGI T IGLTVHLL KKKMPIQNGG ANLCSSFSIC HTFQWHEAMF LLEFFLPLGI ILFCSARIIW SLRQRQMDRH AKIKRAITFI MV VAIVFVI CFLPSVVVRI RIFWLLHTSG TQNCEVYRSV DLAFFITLSF TYMNSMLDPV VYYFSSPSFP NFFSTLINRC LQR KMTGEP DNNRSTSVEL TGDPNKTRGA PEALMANSGE PWSPSYLGPT SP UniProtKB: Hydroxycarboxylic acid receptor 2 |
-分子 #2: scFv16
分子 | 名称: scFv16 / 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: 28.668922 KDa |
組換発現 | 生物種: ![]() ![]() |
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 KAAALEVLFQ GPHHHHHHHH |
-分子 #3: 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: 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: 40.445059 KDa |
組換発現 | 生物種: ![]() ![]() |
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 #4: 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: 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: 39.418086 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR ...文字列: MHHHHHHLEV LFQGPGSSGS 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 #5: 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: 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: 7.861143 KDa |
組換発現 | 生物種: ![]() ![]() |
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 #6: (4aR,5aR)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c...
分子 | 名称: (4aR,5aR)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazole-3-carboxylic acid タイプ: ligand / ID: 6 / コピー数: 1 / 式: XOT |
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分子量 | 理論値: 164.161 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
濃度 | 3.5 mg/mL |
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緩衝液 | pH: 7.5 |
凍結 | 凍結剤: ETHANE-PROPANE |
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電子顕微鏡法
顕微鏡 | FEI TALOS ARCTICA |
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撮影 | フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 平均電子線量: 48.0 e/Å2 |
電子線 | 加速電圧: 200 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): 1.9000000000000001 µm 最小 デフォーカス(公称値): 1.4000000000000001 µm |
実験機器 | ![]() モデル: Talos Arctica / 画像提供: FEI Company |
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画像解析
-原子モデル構築 1
精密化 | プロトコル: FLEXIBLE FIT |
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得られたモデル | ![]() PDB-8utd: |