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基本情報
登録情報 | データベース: PDB / ID: 6w1m | |||||||||
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タイトル | Cryo-EM structure of 5HT3A receptor in presence of Ondansetron | |||||||||
![]() | 5-hydroxytryptamine receptor 3A | |||||||||
![]() | TRANSPORT PROTEIN | |||||||||
機能・相同性 | ![]() Neurotransmitter receptors and postsynaptic signal transmission / serotonin-gated monoatomic cation channel activity / serotonin-activated cation-selective channel complex / serotonin receptor signaling pathway / excitatory extracellular ligand-gated monoatomic ion channel activity / serotonin binding / inorganic cation transmembrane transport / cleavage furrow / transmembrane transporter complex / extracellular ligand-gated monoatomic ion channel activity ...Neurotransmitter receptors and postsynaptic signal transmission / serotonin-gated monoatomic cation channel activity / serotonin-activated cation-selective channel complex / serotonin receptor signaling pathway / excitatory extracellular ligand-gated monoatomic ion channel activity / serotonin binding / inorganic cation transmembrane transport / cleavage furrow / transmembrane transporter complex / extracellular ligand-gated monoatomic ion channel activity / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / transmembrane signaling receptor activity / presynaptic membrane / postsynaptic membrane / neuron projection / axon / neuronal cell body / glutamatergic synapse / synapse / identical protein binding / plasma membrane 類似検索 - 分子機能 | |||||||||
生物種 | ![]() ![]() | |||||||||
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: 3.06 Å | |||||||||
![]() | Basak, S. / Chakrapani, S. | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: High-resolution structures of multiple 5-HTR-setron complexes reveal a novel mechanism of competitive inhibition. 著者: Sandip Basak / Arvind Kumar / Steven Ramsey / Eric Gibbs / Abhijeet Kapoor / Marta Filizola / Sudha Chakrapani / ![]() 要旨: Serotonin receptors (5-HTR) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea ...Serotonin receptors (5-HTR) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea and vomiting associated with radiation and chemotherapies. Structural insights into setron-binding poses and their inhibitory mechanisms are just beginning to emerge. Here, we present high-resolution cryo-EM structures of full-length 5-HTR in complex with palonosetron, ondansetron, and alosetron. Molecular dynamic simulations of these structures embedded in a fully-hydrated lipid environment assessed the stability of ligand-binding poses and drug-target interactions over time. Together with simulation results of apo- and serotonin-bound 5-HTR, the study reveals a distinct interaction fingerprint between the various setrons and binding-pocket residues that may underlie their diverse affinities. In addition, varying degrees of conformational change in the setron-5-HTR structures, throughout the channel and particularly along the channel activation pathway, suggests a novel mechanism of competitive inhibition. #1: ![]() タイトル: Molecular mechanism of setron-mediated inhibition of full-length 5-HT receptor. 著者: Sandip Basak / Yvonne Gicheru / Abhijeet Kapoor / Megan L Mayer / Marta Filizola / Sudha Chakrapani / ![]() 要旨: Serotonin receptor (5-HTR) is the most common therapeutic target to manage the nausea and vomiting during cancer therapies and in the treatment of irritable bowel syndrome. Setrons, a class of ...Serotonin receptor (5-HTR) is the most common therapeutic target to manage the nausea and vomiting during cancer therapies and in the treatment of irritable bowel syndrome. Setrons, a class of competitive antagonists, cause functional inhibition of 5-HTR in the gastrointestinal tract and brainstem, acting as effective anti-emetic agents. Despite their prevalent use, the molecular mechanisms underlying setron binding and inhibition of 5-HTR are not fully understood. Here, we present the structure of granisetron-bound full-length 5-HTR solved by single-particle cryo-electron microscopy to 2.92 Å resolution. The reconstruction reveals the orientation of granisetron in the orthosteric site with unambiguous density for interacting sidechains. Molecular dynamics simulations and electrophysiology confirm the granisetron binding orientation and the residues central for ligand recognition. Comparison of granisetron-bound 5-HTR with the apo and serotonin-bound structures, reveals key insights into the mechanism underlying 5-HTR inhibition. | |||||||||
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構造の表示
ムービー |
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構造ビューア | 分子: ![]() ![]() |
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PDBx/mmCIF形式 | ![]() | 365.5 KB | 表示 | ![]() |
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PDB形式 | ![]() | 313.7 KB | 表示 | ![]() |
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その他 | ![]() |
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アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
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-関連構造データ
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リンク
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集合体
登録構造単位 | ![]()
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要素
#1: タンパク質 | 分子量: 52042.121 Da / 分子数: 5 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() 発現宿主: ![]() ![]() 参照: UniProt: Q8K1F4, UniProt: P23979*PLUS #2: 多糖 | 2-acetamido-2-deoxy-beta-D-glucopyranose-(4-4)-2-acetamido-2-deoxy-beta-D-glucopyranose タイプ: oligosaccharide / 分子量: 424.401 Da / 分子数: 5 / 由来タイプ: 組換発現 #3: 多糖 | beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose #4: 多糖 | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose #5: 化合物 | ChemComp-S87 / 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 |
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試料調製
構成要素 | 名称: Serotonin receptor / タイプ: COMPLEX / Entity ID: #1 / 由来: RECOMBINANT |
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分子量 | 値: 0.27 MDa / 実験値: NO |
由来(天然) | 生物種: ![]() ![]() |
由来(組換発現) | 生物種: ![]() ![]() |
緩衝液 | pH: 8 |
試料 | 濃度: 3 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
試料支持 | グリッドのタイプ: Quantifoil R1.2/1.3 |
急速凍結 | 装置: FEI VITROBOT MARK I / 凍結剤: ETHANE / 湿度: 100 % / 凍結前の試料温度: 277 K / 詳細: blot for 2.5 seconds |
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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: ![]() |
電子レンズ | モード: BRIGHT FIELD / 倍率(公称値): 105000 X / Cs: 2.7 mm / C2レンズ絞り径: 70 µm |
試料ホルダ | 凍結剤: NITROGEN |
撮影 | 電子線照射量: 50 e/Å2 / 検出モード: SUPER-RESOLUTION / フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 実像数: 2530 |
画像スキャン | 動画フレーム数/画像: 30 / 利用したフレーム数/画像: 1-30 |
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解析
ソフトウェア | 名称: PHENIX / バージョン: 1.13_2998: / 分類: 精密化 | ||||||||||||||||||||||||||||||||||||
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EMソフトウェア |
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||
粒子像の選択 | 選択した粒子像数: 449628 | ||||||||||||||||||||||||||||||||||||
対称性 | 点対称性: C5 (5回回転対称) | ||||||||||||||||||||||||||||||||||||
3次元再構成 | 解像度: 3.06 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 67333 / 対称性のタイプ: POINT | ||||||||||||||||||||||||||||||||||||
原子モデル構築 | B value: 50 / プロトコル: OTHER / 空間: REAL |