+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8jqr | ||||||
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タイトル | Structure of human TRPV1 in complex with antagonist | ||||||
要素 | Transient receptor potential cation channel subfamily V member 1,PreScission Site,Green fluorescent protein | ||||||
キーワード | MEMBRANE PROTEIN / channel | ||||||
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 / detection of chemical stimulus involved in sensory perception of pain / smooth muscle contraction involved in micturition / cellular response to temperature stimulus / cellular response to acidic pH ...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 / detection of chemical stimulus involved in sensory perception of pain / smooth muscle contraction involved in micturition / cellular response to temperature stimulus / cellular response to acidic pH / fever generation / detection of temperature stimulus involved in thermoception / thermoception / negative regulation of systemic arterial blood pressure / glutamate secretion / chloride channel regulator activity / dendritic spine membrane / TRP channels / excitatory extracellular ligand-gated monoatomic ion channel activity / cellular response to ATP / negative regulation of heart rate / cellular response to alkaloid / calcium ion import across plasma membrane / 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 / voltage-gated calcium channel activity / extracellular ligand-gated monoatomic ion 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 / positive regulation of nitric oxide biosynthetic process / transmembrane signaling receptor activity / 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 / identical protein binding / membrane / metal ion binding / plasma membrane 類似検索 - 分子機能 | ||||||
生物種 | Homo sapiens (ヒト) Pseudotevenvirus RB43 (ウイルス) | ||||||
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: 2.75 Å | ||||||
データ登録者 | Fan, J. / Lei, X. | ||||||
資金援助 | 中国, 1件
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引用 | ジャーナル: Nat Commun / 年: 2024 タイトル: Structural basis of TRPV1 inhibition by SAF312 and cholesterol. 著者: Junping Fan / Han Ke / Jing Lei / Jin Wang / Makoto Tominaga / Xiaoguang Lei / 要旨: Transient Receptor Potential Vanilloid 1 (TRPV1) plays a central role in pain sensation and is thus an attractive pharmacological drug target. SAF312 is a potent, selective, and non-competitive ...Transient Receptor Potential Vanilloid 1 (TRPV1) plays a central role in pain sensation and is thus an attractive pharmacological drug target. SAF312 is a potent, selective, and non-competitive antagonist of TRPV1 and shows promising potential in treating ocular surface pain. However, the precise mechanism by which SAF312 inhibits TRPV1 remains poorly understood. Here, we present the cryo-EM structure of human TRPV1 in complex with SAF312, elucidating the structural foundation of its antagonistic effects on TRPV1. SAF312 binds to the vanilloid binding pocket, preventing conformational changes in S4 and S5 helices, which are essential for channel gating. Unexpectedly, a putative cholesterol was found to contribute to SAF312's inhibition. Complemented by mutagenesis experiments and molecular dynamics simulations, our research offers substantial mechanistic insights into the regulation of TRPV1 by SAF312, highlighting the interplay between the antagonist and cholesterol in modulating TRPV1 function. This work not only expands our understanding of TRPV1 inhibition by SAF312 but also lays the groundwork for further developments in the design and optimization of TRPV1-related therapies. | ||||||
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 | 8jqr.cif.gz | 419.9 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb8jqr.ent.gz | 321.5 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8jqr.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 | 8jqr_validation.pdf.gz | 1.6 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 8jqr_full_validation.pdf.gz | 1.6 MB | 表示 | |
XML形式データ | 8jqr_validation.xml.gz | 66.7 KB | 表示 | |
CIF形式データ | 8jqr_validation.cif.gz | 96.8 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/jq/8jqr ftp://data.pdbj.org/pub/pdb/validation_reports/jq/8jqr | HTTPS FTP |
-関連構造データ
関連構造データ | 36577MC 8x94C 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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-要素
#1: タンパク質 | 分子量: 125297.734 Da / 分子数: 4 / 由来タイプ: 組換発現 詳細: The section (840-842) is the cloning site.The domain (843-850) is PreScission Site.The domain (851-1084) is corresponding to this sfGFP (462-695 amino acids, GenBank: ALP48449.1). The domain ...詳細: The section (840-842) is the cloning site.The domain (843-850) is PreScission Site.The domain (851-1084) is corresponding to this sfGFP (462-695 amino acids, GenBank: ALP48449.1). The domain (1085-1112) is the expression Tag. 由来: (組換発現) Homo sapiens (ヒト), (組換発現) Pseudotevenvirus RB43 (ウイルス) 遺伝子: TRPV1, VR1 / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: Q8NER1 #2: 化合物 | ChemComp-EZI / 分子量: 305.331 Da / 分子数: 4 / 由来タイプ: 合成 / 式: C18H15N3O2 / タイプ: SUBJECT OF INVESTIGATION #3: 化合物 | ChemComp-CLR / 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: TRPV1 / タイプ: COMPLEX / Entity ID: #1 / 由来: MULTIPLE SOURCES |
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分子量 | 値: 0.36 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: HEK293 |
緩衝液 | pH: 8 |
試料 | 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 FIELD / 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 |
撮影 | 電子線照射量: 60 e/Å2 フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) |
-解析
CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
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3次元再構成 | 解像度: 2.75 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 239934 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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