+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8gf9 | ||||||||||||||||||
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タイトル | Cryo-EM structure of human TRPV1 in cNW11 nanodisc and POPC:POPE:POPG lipids | ||||||||||||||||||
要素 | Transient receptor potential cation channel subfamily V member 1TRPV1 | ||||||||||||||||||
キーワード | MEMBRANE PROTEIN (膜タンパク質) / transient receptor potential V family member 1 / TRP / apo / human (ヒト) / channel / TRPV1 (TRPV1) / TRP channels (TRPチャネル) / pain (疼痛) / cNW11 / nanodiscs / thermo-TRP / temperature sensation / vanilloid / POPC:POPE:POPG | ||||||||||||||||||
機能・相同性 | 機能・相同性情報 chemosensory behavior / temperature-gated ion channel activity / response to capsazepine / negative regulation of establishment of blood-brain barrier / sensory perception of mechanical stimulus / peptide secretion / excitatory extracellular ligand-gated monoatomic ion channel activity / detection of chemical stimulus involved in sensory perception of pain / cellular response to temperature stimulus / smooth muscle contraction involved in micturition ...chemosensory behavior / temperature-gated ion channel activity / response to capsazepine / negative regulation of establishment of blood-brain barrier / sensory perception of mechanical stimulus / peptide secretion / excitatory extracellular ligand-gated monoatomic ion channel activity / detection of chemical stimulus involved in sensory perception of pain / cellular response to temperature stimulus / smooth muscle contraction involved in micturition / cellular response to acidic pH / thermoception / fever generation / detection of temperature stimulus involved in thermoception / glutamate secretion / dendritic spine membrane / negative regulation of systemic arterial blood pressure / chloride channel regulator activity / TRPチャネル / extracellular ligand-gated monoatomic ion channel activity / cellular response to ATP / negative regulation of heart rate / cellular response to alkaloid / behavioral response to pain / diet induced thermogenesis / intracellularly gated calcium channel activity / detection of temperature stimulus involved in sensory perception of pain / negative regulation of mitochondrial membrane potential / calcium ion import across plasma membrane / voltage-gated calcium channel activity / phosphatidylinositol binding / cellular response to nerve growth factor stimulus / calcium ion transmembrane transport / phosphoprotein binding / microglial cell activation / calcium channel activity / lipid metabolic process / response to peptide hormone / transmembrane signaling receptor activity / positive regulation of nitric oxide biosynthetic process / cellular response to tumor necrosis factor / cellular response to heat / positive regulation of cytosolic calcium ion concentration / postsynaptic membrane / protein homotetramerization / cell surface receptor signaling pathway / calmodulin binding / positive regulation of apoptotic process / external side of plasma membrane / neuronal cell body / negative regulation of transcription by RNA polymerase II / ATP binding / 生体膜 / identical protein binding / metal ion binding / 細胞膜 類似検索 - 分子機能 | ||||||||||||||||||
生物種 | Homo sapiens (ヒト) | ||||||||||||||||||
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: 2.58 Å | ||||||||||||||||||
データ登録者 | Neuberger, A. / Nadezhdin, K.D. / Sobolevsky, A.I. | ||||||||||||||||||
資金援助 | 米国, ドイツ, 5件
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引用 | ジャーナル: Nat Commun / 年: 2023 タイトル: Human TRPV1 structure and inhibition by the analgesic SB-366791. 著者: Arthur Neuberger / Mai Oda / Yury A Nikolaev / Kirill D Nadezhdin / Elena O Gracheva / Sviatoslav N Bagriantsev / Alexander I Sobolevsky / 要旨: Pain therapy has remained conceptually stagnant since the opioid crisis, which highlighted the dangers of treating pain with opioids. An alternative addiction-free strategy to conventional painkiller- ...Pain therapy has remained conceptually stagnant since the opioid crisis, which highlighted the dangers of treating pain with opioids. An alternative addiction-free strategy to conventional painkiller-based treatment is targeting receptors at the origin of the pain pathway, such as transient receptor potential (TRP) ion channels. Thus, a founding member of the vanilloid subfamily of TRP channels, TRPV1, represents one of the most sought-after pain therapy targets. The need for selective TRPV1 inhibitors extends beyond pain treatment, to other diseases associated with this channel, including psychiatric disorders. Here we report the cryo-electron microscopy structures of human TRPV1 in the apo state and in complex with the TRPV1-specific nanomolar-affinity analgesic antagonist SB-366791. SB-366791 binds to the vanilloid site and acts as an allosteric hTRPV1 inhibitor. SB-366791 binding site is supported by mutagenesis combined with electrophysiological recordings and can be further explored to design new drugs targeting TRPV1 in disease conditions. | ||||||||||||||||||
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 | 8gf9.cif.gz | 845.5 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb8gf9.ent.gz | 708.9 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8gf9.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/gf/8gf9 ftp://data.pdbj.org/pub/pdb/validation_reports/gf/8gf9 | HTTPS FTP |
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-関連構造データ
関連構造データ | 29982MC 8gf8C 8gfaC C: 同じ文献を引用 (文献) M: このデータのモデリングに利用したマップデータ |
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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
#1: タンパク質 | 分子量: 124575.281 Da / 分子数: 4 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: TRPV1, VR1 / プラスミド: pEG BacMam / 細胞株 (発現宿主): HEK293 / 発現宿主: Homo sapiens (ヒト) / Variant (発現宿主): suspension-adapted cells / 参照: UniProt: Q8NER1 #2: 化合物 | ChemComp-POV / ( #3: 化合物 | ChemComp-8IJ / ( #4: 化合物 | #5: 水 | ChemComp-HOH / | 研究の焦点であるリガンドがあるか | N | |
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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: sample 1 / タイプ: COMPLEX / Entity ID: #1 / 由来: RECOMBINANT | ||||||||||||||||||||
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分子量 | 値: 0.09497 MDa / 実験値: NO | ||||||||||||||||||||
由来(天然) | 生物種: Homo sapiens (ヒト) | ||||||||||||||||||||
由来(組換発現) | 生物種: Homo sapiens (ヒト) / 細胞: Human embryonic kidney 293 / プラスミド: pEG BacMam | ||||||||||||||||||||
緩衝液 | pH: 8 | ||||||||||||||||||||
緩衝液成分 |
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試料 | 濃度: 2.5 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES 詳細: human TRPV1 reconstituted in cNW11 lipid nanodisc (POPC:POPE:POPG) | ||||||||||||||||||||
試料支持 | グリッドの材料: GOLD / グリッドのサイズ: 300 divisions/in. / グリッドのタイプ: UltrAuFoil R1.2/1.3 | ||||||||||||||||||||
急速凍結 | 装置: FEI VITROBOT MARK IV / 凍結剤: ETHANE / 湿度: 100 % / 凍結前の試料温度: 277 K |
-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: TFS 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): 800 nm / Cs: 2.7 mm |
撮影 | 平均露光時間: 2 sec. / 電子線照射量: 60 e/Å2 / フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 撮影したグリッド数: 1 / 実像数: 16062 |
画像スキャン | 横: 5760 / 縦: 4092 |
-解析
EMソフトウェア |
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CTF補正 | タイプ: NONE | ||||||||||||||||||||||||||||||||||||
粒子像の選択 | 選択した粒子像数: 6558023 | ||||||||||||||||||||||||||||||||||||
3次元再構成 | 解像度: 2.58 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 778428 / 対称性のタイプ: POINT | ||||||||||||||||||||||||||||||||||||
原子モデル構築 | 空間: REAL | ||||||||||||||||||||||||||||||||||||
拘束条件 |
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