+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8tr2 | ||||||||||||
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タイトル | mGluR3 in the presence of the agonist LY379268 | ||||||||||||
要素 | Metabotropic glutamate receptor 3 | ||||||||||||
キーワード | MEMBRANE PROTEIN / GPCR / synaptic protein | ||||||||||||
機能・相同性 | 機能・相同性情報 Class C/3 (Metabotropic glutamate/pheromone receptors) / group II metabotropic glutamate receptor activity / astrocyte projection / G protein-coupled glutamate receptor signaling pathway / G alpha (i) signalling events / postsynaptic modulation of chemical synaptic transmission / calcium channel regulator activity / regulation of synaptic transmission, glutamatergic / sensory perception of pain / modulation of chemical synaptic transmission ...Class C/3 (Metabotropic glutamate/pheromone receptors) / group II metabotropic glutamate receptor activity / astrocyte projection / G protein-coupled glutamate receptor signaling pathway / G alpha (i) signalling events / postsynaptic modulation of chemical synaptic transmission / calcium channel regulator activity / regulation of synaptic transmission, glutamatergic / sensory perception of pain / modulation of chemical synaptic transmission / presynaptic membrane / gene expression / scaffold protein binding / postsynaptic membrane / postsynapse / dendritic spine / postsynaptic density / neuron projection / axon / glutamatergic synapse / plasma membrane 類似検索 - 分子機能 | ||||||||||||
生物種 | Rattus norvegicus (ドブネズミ) | ||||||||||||
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: 3.5 Å | ||||||||||||
データ登録者 | Strauss, A. / Levitz, J. | ||||||||||||
資金援助 | 米国, 3件
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引用 | ジャーナル: bioRxiv / 年: 2023 タイトル: Structural basis of allosteric modulation of metabotropic glutamate receptor activation and desensitization. 要旨: The metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled receptors which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) ...The metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled receptors which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) to transmembrane domains (TMDs) to drive intracellular signaling. Pharmacologically, mGluRs can be targeted either at the LBDs by glutamate and synthetic orthosteric compounds or at the TMDs by allosteric modulators. Despite the potential of allosteric TMD-targeting compounds as therapeutics, an understanding of the functional and structural basis of their effects on mGluRs is limited. Here we use a battery of approaches to dissect the distinct functional and structural effects of orthosteric versus allosteric ligands. We find using electrophysiological and live cell imaging assays that both agonists and positive allosteric modulators (PAMs) can drive activation and desensitization of mGluRs. The effects of PAMs are pleiotropic, including both the ability to boost the maximal response to orthosteric agonists and to serve independently as desensitization-biased agonists across mGluR subtypes. Conformational sensors reveal PAM-driven inter-subunit re-arrangements at both the LBD and TMD. Motivated by this, we determine cryo-electron microscopy structures of mGluR3 in the presence of either an agonist or antagonist alone or in combination with a PAM. These structures reveal PAM-driven re-shaping of intra- and inter-subunit conformations and provide evidence for a rolling TMD dimer interface activation pathway that controls G protein and beta-arrestin coupling. HIGHLIGHTS: -Agonists and PAMs drive mGluR activation, desensitization, and endocytosis-PAMs are desensitization-biased and synergistic with agonists-Four combinatorial ligand conditions reveal an ...HIGHLIGHTS: -Agonists and PAMs drive mGluR activation, desensitization, and endocytosis-PAMs are desensitization-biased and synergistic with agonists-Four combinatorial ligand conditions reveal an ensemble of full-length mGluR structures with novel interfaces-Activation and desensitization involve rolling TMD interfaces which are re-shaped by PAM. | ||||||||||||
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 | 8tr2.cif.gz | 256.7 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb8tr2.ent.gz | 191.1 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8tr2.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 | 8tr2_validation.pdf.gz | 1.2 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 8tr2_full_validation.pdf.gz | 1.2 MB | 表示 | |
XML形式データ | 8tr2_validation.xml.gz | 57 KB | 表示 | |
CIF形式データ | 8tr2_validation.cif.gz | 85.1 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/tr/8tr2 ftp://data.pdbj.org/pub/pdb/validation_reports/tr/8tr2 | HTTPS FTP |
-関連構造データ
-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: 103161.555 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) Rattus norvegicus (ドブネズミ) / 遺伝子: Grm3 / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: P31422 #2: 化合物 | 分子量: 187.150 Da / 分子数: 2 / 由来タイプ: 合成 / 式: C7H9NO5 #3: 化合物 | ChemComp-CA / 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: Metabotropic Glutamate Receptor 3 dimer / タイプ: COMPLEX / Entity ID: #1 / 由来: RECOMBINANT | |||||||||||||||||||||
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分子量 | 値: 0.26 MDa / 実験値: NO | |||||||||||||||||||||
由来(天然) | 生物種: Rattus norvegicus (ドブネズミ) | |||||||||||||||||||||
由来(組換発現) | 生物種: Homo sapiens (ヒト) | |||||||||||||||||||||
緩衝液 |
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試料 |
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試料支持 | グリッドの材料: GOLD / グリッドのタイプ: UltrAuFoil R1.2/1.3 | |||||||||||||||||||||
急速凍結 |
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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: 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): 700 nm / アライメント法: BASIC |
試料ホルダ | 凍結剤: NITROGEN 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER |
撮影 | 電子線照射量: 58 e/Å2 / 検出モード: COUNTING フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) |
-解析
EMソフトウェア | 名称: PHENIX / バージョン: 1.21_5207 / カテゴリ: モデル精密化 |
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION |
3次元再構成 | 解像度: 3.5 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 133004 / 対称性のタイプ: POINT |
原子モデル構築 | プロトコル: AB INITIO MODEL / 空間: REAL |
精密化 | 交差検証法: NONE |