+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8tr8 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
タイトル | Cryo-EM structure of the rat P2X7 receptor in complex with the allosteric antagonist AZD9056 | |||||||||
要素 | P2X purinoceptor 7 | |||||||||
キーワード | MEMBRANE PROTEIN / Ion Channel / Ligand-gate Ion Channel / P2X Receptor / Allosteric Antagonist / High-Affinity Agonist | |||||||||
機能・相同性 | 機能・相同性情報 Platelet homeostasis / The NLRP3 inflammasome / regulation of presynaptic dense core granule exocytosis / positive regulation of lymphocyte apoptotic process / positive regulation of bleb assembly / NAD transport / phagolysosome assembly / Elevation of cytosolic Ca2+ levels / phospholipid transfer to membrane / positive regulation of cytoskeleton organization ...Platelet homeostasis / The NLRP3 inflammasome / regulation of presynaptic dense core granule exocytosis / positive regulation of lymphocyte apoptotic process / positive regulation of bleb assembly / NAD transport / phagolysosome assembly / Elevation of cytosolic Ca2+ levels / phospholipid transfer to membrane / positive regulation of cytoskeleton organization / purinergic nucleotide receptor signaling pathway / purinergic nucleotide receptor activity / extracellularly ATP-gated monoatomic cation channel activity / lymphocyte apoptotic process / positive regulation of monoatomic ion transmembrane transport / gamma-aminobutyric acid secretion / pore complex assembly / positive regulation of interleukin-1 alpha production / plasma membrane organization / negative regulation of cell volume / positive regulation of gamma-aminobutyric acid secretion / ATP export / bleb / collagen metabolic process / plasma membrane phospholipid scrambling / response to fluid shear stress / T cell apoptotic process / positive regulation of prostaglandin secretion / bleb assembly / positive regulation of T cell apoptotic process / mitochondrial depolarization / vesicle budding from membrane / prostaglandin secretion / ceramide biosynthetic process / cellular response to dsRNA / programmed cell death / positive regulation of glutamate secretion / positive regulation of ossification / cell volume homeostasis / glutamate secretion / skeletal system morphogenesis / negative regulation of bone resorption / phospholipid translocation / positive regulation of macrophage cytokine production / positive regulation of calcium ion transport into cytosol / response to ATP / positive regulation of mitochondrial depolarization / response to zinc ion / T cell homeostasis / cellular response to organic cyclic compound / monoatomic cation transport / synaptic vesicle exocytosis / membrane depolarization / membrane protein ectodomain proteolysis / neuronal action potential / protein secretion / negative regulation of MAPK cascade / response to electrical stimulus / positive regulation of bone mineralization / response to mechanical stimulus / T cell proliferation / regulation of sodium ion transport / extrinsic apoptotic signaling pathway / release of sequestered calcium ion into cytosol / homeostasis of number of cells within a tissue / sensory perception of pain / positive regulation of glycolytic process / reactive oxygen species metabolic process / protein serine/threonine kinase activator activity / positive regulation of interleukin-1 beta production / mitochondrion organization / establishment of localization in cell / positive regulation of protein secretion / apoptotic signaling pathway / calcium ion transmembrane transport / lipopolysaccharide binding / response to bacterium / neuromuscular junction / cell morphogenesis / protein catabolic process / response to organic cyclic compound / terminal bouton / T cell mediated cytotoxicity / protein processing / positive regulation of interleukin-6 production / response to calcium ion / channel activity / positive regulation of T cell mediated cytotoxicity / calcium ion transport / MAPK cascade / cell-cell junction / nuclear envelope / signaling receptor activity / gene expression / scaffold protein binding / postsynapse / response to lipopolysaccharide / positive regulation of MAPK cascade / cell surface receptor signaling pathway / defense response to Gram-positive bacterium 類似検索 - 分子機能 | |||||||||
生物種 | Rattus (ネズミ) | |||||||||
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: 2.21 Å | |||||||||
データ登録者 | Oken, A.C. / Ditter, I.A. / Lisi, N.E. / Krishnamurthy, I. / McCarthy, A.E. / Godsey, M.H. / Mansoor, S.E. | |||||||||
資金援助 | 米国, 2件
| |||||||||
引用 | ジャーナル: Sci Adv / 年: 2024 タイトル: P2X receptors exhibit at least three modes of allosteric antagonism. 著者: Adam C Oken / Ismayn A Ditter / Nicolas E Lisi / Ipsita Krishnamurthy / Michael H Godsey / Steven E Mansoor / 要旨: P2X receptors are trimeric ion channels activated by adenosine triphosphate (ATP) that contribute to pathophysiological processes ranging from asthma to neuropathic pain and neurodegeneration. A ...P2X receptors are trimeric ion channels activated by adenosine triphosphate (ATP) that contribute to pathophysiological processes ranging from asthma to neuropathic pain and neurodegeneration. A number of small-molecule antagonists have been identified for these important pharmaceutical targets. However, the molecular pharmacology of P2X receptors is poorly understood because of the chemically disparate nature of antagonists and their differential actions on the seven constituent subtypes. Here, we report high-resolution cryo-electron microscopy structures of the homomeric rat P2X receptor bound to five previously known small-molecule allosteric antagonists and a sixth antagonist that we identify. Our structural, biophysical, and electrophysiological data define the molecular determinants of allosteric antagonism in this pharmacologically relevant receptor, revealing three distinct classes of antagonists that we call shallow, deep, and starfish. Starfish binders, exemplified by the previously unidentified antagonist methyl blue, represent a unique class of inhibitors with distinct functional properties that could be exploited to develop potent P2X ligands with substantial clinical impact. | |||||||||
履歴 |
|
-構造の表示
構造ビューア | 分子: MolmilJmol/JSmol |
---|
-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 8tr8.cif.gz | 573.4 KB | 表示 | PDBx/mmCIF形式 |
---|---|---|---|---|
PDB形式 | pdb8tr8.ent.gz | 481.1 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8tr8.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
文書・要旨 | 8tr8_validation.pdf.gz | 1.7 MB | 表示 | wwPDB検証レポート |
---|---|---|---|---|
文書・詳細版 | 8tr8_full_validation.pdf.gz | 1.7 MB | 表示 | |
XML形式データ | 8tr8_validation.xml.gz | 72.6 KB | 表示 | |
CIF形式データ | 8tr8_validation.cif.gz | 106.3 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/tr/8tr8 ftp://data.pdbj.org/pub/pdb/validation_reports/tr/8tr8 | HTTPS FTP |
-関連構造データ
関連構造データ | 41573MC 8tr6C 8tr7C 8traC 8trbC 8trkC 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) |
---|---|
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 |
|
---|---|
1 |
|
-要素
-タンパク質 / 糖 , 2種, 9分子 ABC
#1: タンパク質 | 分子量: 68472.461 Da / 分子数: 3 / 由来タイプ: 組換発現 / 由来: (組換発現) Rattus (ネズミ) / 遺伝子: P2rx7 / 細胞株 (発現宿主): HEK293 GNTI- / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: Q64663 #5: 糖 | ChemComp-NAG / |
---|
-非ポリマー , 6種, 380分子
#2: 化合物 | 分子量: 419.000 Da / 分子数: 3 / 由来タイプ: 合成 / 式: C24H35ClN2O2 / タイプ: SUBJECT OF INVESTIGATION #3: 化合物 | #4: 化合物 | ChemComp-ZN / #6: 化合物 | ChemComp-PLM / #7: 化合物 | ChemComp-NA / | #8: 水 | ChemComp-HOH / | |
---|
-詳細
研究の焦点であるリガンドがあるか | Y |
---|---|
Has protein modification | Y |
-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
---|---|
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: Membrane protein / タイプ: COMPLEX / Entity ID: #1 / 由来: RECOMBINANT |
---|---|
由来(天然) | 生物種: Rattus (ネズミ) |
由来(組換発現) | 生物種: Homo sapiens (ヒト) / 細胞: HEK293 GNTI- |
緩衝液 | pH: 7 |
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
急速凍結 | 装置: FEI VITROBOT MARK IV / 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 |
---|---|
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 FIELD / 倍率(公称値): 130000 X / 最大 デフォーカス(公称値): 1700 nm / 最小 デフォーカス(公称値): 1000 nm / Cs: 2.7 mm / C2レンズ絞り径: 50 µm |
試料ホルダ | 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER |
撮影 | 電子線照射量: 44 e/Å2 / フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 実像数: 10745 |
電子光学装置 | エネルギーフィルタースリット幅: 20 eV |
-解析
CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
対称性 | 点対称性: C3 (3回回転対称) | ||||||||||||||||||||||||
3次元再構成 | 解像度: 2.21 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 481019 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
|