+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-38161 | |||||||||
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タイトル | Structure of human TRPV1 in complex with antagonist --protein purified without CHS | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | channel / MEMBRANE PROTEIN | |||||||||
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) / synthetic construct (人工物) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.55 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
添付画像 |
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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 | emd_38161.map.gz | 117.8 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-38161-v30.xml emd-38161.xml | 14.7 KB 14.7 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_38161.png | 63.9 KB | ||
Filedesc metadata | emd-38161.cif.gz | 6.1 KB | ||
その他 | emd_38161_half_map_1.map.gz emd_38161_half_map_2.map.gz | 115.2 MB 115.2 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-38161 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-38161 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_38161_validation.pdf.gz | 843.7 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_38161_full_validation.pdf.gz | 843.3 KB | 表示 | |
XML形式データ | emd_38161_validation.xml.gz | 14 KB | 表示 | |
CIF形式データ | emd_38161_validation.cif.gz | 16.4 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-38161 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-38161 | HTTPS FTP |
-関連構造データ
関連構造データ | 8x94MC 8jqrC 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 (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
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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「今月の分子」の関連する項目 |
-マップ
ファイル | ダウンロード / ファイル: emd_38161.map.gz / 形式: CCP4 / 大きさ: 125 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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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: 0.85 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: #1
ファイル | emd_38161_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: #2
ファイル | emd_38161_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 |
-試料の構成要素
-全体 : TRPV1
全体 | 名称: TRPV1 |
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要素 |
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-超分子 #1: TRPV1
超分子 | 名称: TRPV1 / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1 |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 360 KDa |
-分子 #1: Transient receptor potential cation channel subfamily V member 1,...
分子 | 名称: Transient receptor potential cation channel subfamily V member 1,Green fluorescent protein タイプ: protein_or_peptide / ID: 1 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. コピー数: 4 / 光学異性体: LEVO |
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由来(天然) | 生物種: synthetic construct (人工物) |
分子量 | 理論値: 125.297734 KDa |
組換発現 | 生物種: Homo sapiens (ヒト) |
配列 | 文字列: MKKWSSTDLG AAADPLQKDT CPDPLDGDPN SRPPPAKPQL STAKSRTRLF GKGDSEEAFP VDCPHEEGEL DSCPTITVSP VITIQRPGD GPTGARLLSQ DSVAASTEKT LRLYDRRSIF EAVAQNNCQD LESLLLFLQK SKKHLTDNEF KDPETGKTCL L KAMLNLHD ...文字列: MKKWSSTDLG AAADPLQKDT CPDPLDGDPN SRPPPAKPQL STAKSRTRLF GKGDSEEAFP VDCPHEEGEL DSCPTITVSP VITIQRPGD GPTGARLLSQ DSVAASTEKT LRLYDRRSIF EAVAQNNCQD LESLLLFLQK SKKHLTDNEF KDPETGKTCL L KAMLNLHD GQNTTIPLLL EIARQTDSLK ELVNASYTDS YYKGQTALHI AIERRNMALV TLLVENGADV QAAAHGDFFK KT KGRPGFY FGELPLSLAA CTNQLGIVKF LLQNSWQTAD ISARDSVGNT VLHALVEVAD NTADNTKFVT SMYNEILMLG AKL HPTLKL EELTNKKGMT PLALAAGTGK IGVLAYILQR EIQEPECRHL SRKFTEWAYG PVHSSLYDLS CIDTCEKNSV LEVI AYSSS ETPNRHDMLL VEPLNRLLQD KWDRFVKRIF YFNFLVYCLY MIIFTMAAYY RPVDGLPPFK MEKTGDYFRV TGEIL SVLG GVYFFFRGIQ YFLQRRPSMK TLFVDSYSEM LFFLQSLFML ATVVLYFSHL KEYVASMVFS LALGWTNMLY YTRGFQ QMG IYAVMIEKMI LRDLCRFMFV YIVFLFGFST AVVTLIEDGK NDSLPSESTS HRWRGPACRP PDSSYNSLYS TCLELFK FT IGMGDLEFTE NYDFKAVFII LLLAYVILTY ILLLNMLIAL MGETVNKIAQ ESKNIWKLQR AITILDTEKS FLKCMRKA F RSGKLLQVGY TPDGKDDYRW CFRVDEVNWT TWNTNVGIIN EDPGNCEGVK RTLSFSLRSS RVSGRHWKNF ALVPLLREA SARDRQSAQP EEVYLRQFSG SLKPEDAEVF KSPAASGEKA AALEVLFQGP SKGEELFTGV VPILVELDGD VNGHKFSVRG EGEGDATNG KLTLKFICTT GKLPVPWPTL VTTLTYGVQC FSRYPDHMKR HDFFKSAMPE GYVQERTISF KDDGTYKTRA E VKFEGDTL VNRIELKGID FKEDGNILGH KLEYNFNSHN VYITADKQKN GIKANFKIRH NVEDGSVQLA DHYQQNTPIG DG PVLLPDN HYLSTQSVLS KDPNEKRDHM VLLEFVTAAG ITHGMDEWSH PQFEKGGGSG GGSGGSAWSH PQFEK UniProtKB: Transient receptor potential cation channel subfamily V member 1 |
-分子 #2: 4-(7-Hydroxy-2-isopropyl-4-oxoquinazolin-3(4H)-yl)benzonitrile
分子 | 名称: 4-(7-Hydroxy-2-isopropyl-4-oxoquinazolin-3(4H)-yl)benzonitrile タイプ: ligand / ID: 2 / コピー数: 4 / 式: EZI |
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分子量 | 理論値: 305.331 Da |
-分子 #3: CHOLESTEROL
分子 | 名称: CHOLESTEROL / タイプ: ligand / ID: 3 / コピー数: 4 / 式: CLR |
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分子量 | 理論値: 386.654 Da |
Chemical component information | ChemComp-CLR: |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
緩衝液 | pH: 8 |
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凍結 | 凍結剤: ETHANE |
-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 K3 (6k 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: FIELD EMISSION GUN |
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): 2.0 µm / 最小 デフォーカス(公称値): 1.0 µm |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
-画像解析
初期モデル | モデルのタイプ: OTHER |
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最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 2.55 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 183350 |
初期 角度割当 | タイプ: RANDOM ASSIGNMENT |
最終 角度割当 | タイプ: MAXIMUM LIKELIHOOD |