+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8szg | ||||||
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タイトル | Cryo-EM structure of cinacalcet-bound human calcium-sensing receptor CaSR-Gq complex in lipid nanodiscs | ||||||
要素 |
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キーワード | SIGNALING PROTEIN / Family C GPCR / Calcium-sensing Receptor (CaSR) / Heterotrimeric G protein / Cryo-EM / Lipid Nanodiscs / Positive Allosteric Modulator / Membrane Protein | ||||||
機能・相同性 | 機能・相同性情報 bile acid secretion / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / chemosensory behavior / response to fibroblast growth factor / PLC beta mediated events / phospholipase C-activating dopamine receptor signaling pathway / entrainment of circadian clock / cellular response to peptide / regulation of platelet activation ...bile acid secretion / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / chemosensory behavior / response to fibroblast growth factor / PLC beta mediated events / phospholipase C-activating dopamine receptor signaling pathway / entrainment of circadian clock / cellular response to peptide / regulation of platelet activation / cellular response to vitamin D / phosphatidylinositol phospholipase C activity / phototransduction, visible light / Class C/3 (Metabotropic glutamate/pheromone receptors) / calcium ion import / glutamate receptor signaling pathway / : / regulation of canonical Wnt signaling pathway / positive regulation of positive chemotaxis / cellular response to low-density lipoprotein particle stimulus / fat pad development / cellular response to hepatocyte growth factor stimulus / amino acid binding / branching morphogenesis of an epithelial tube / positive regulation of calcium ion import / action potential / regulation of calcium ion transport / positive regulation of vasoconstriction / detection of calcium ion / photoreceptor outer segment / anatomical structure morphogenesis / ossification / axon terminus / JNK cascade / chloride transmembrane transport / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / GTPase activator activity / response to ischemia / G protein-coupled receptor binding / G protein-coupled receptor activity / cellular response to glucose stimulus / negative regulation of protein kinase activity / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / vasodilation / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / positive regulation of insulin secretion / Thromboxane signalling through TP receptor / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / intracellular calcium ion homeostasis / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / integrin binding / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / blood coagulation / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / cellular response to hypoxia / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / basolateral plasma membrane / G alpha (i) signalling events / nuclear membrane / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling 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: 3.6 Å | ||||||
データ登録者 | He, F. / Wu, C. / Gao, Y. / Skiniotis, G. | ||||||
資金援助 | 米国, 1件
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引用 | ジャーナル: Nature / 年: 2024 タイトル: Allosteric modulation and G-protein selectivity of the Ca-sensing receptor. 著者: Feng He / Cheng-Guo Wu / Yang Gao / Sabrina N Rahman / Magda Zaoralová / Makaía M Papasergi-Scott / Ting-Jia Gu / Michael J Robertson / Alpay B Seven / Lingjun Li / Jesper M Mathiesen / Georgios Skiniotis / 要旨: The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor (GPCR) that has a central role in regulating systemic calcium homeostasis. Here we use cryo-electron microscopy and ...The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor (GPCR) that has a central role in regulating systemic calcium homeostasis. Here we use cryo-electron microscopy and functional assays to investigate the activation of human CaSR embedded in lipid nanodiscs and its coupling to functional G versus G proteins in the presence and absence of the calcimimetic drug cinacalcet. High-resolution structures show that both G and G drive additional conformational changes in the activated CaSR dimer to stabilize a more extensive asymmetric interface of the seven-transmembrane domain (7TM) that involves key protein-lipid interactions. Selective G and G coupling by the receptor is achieved through substantial rearrangements of intracellular loop 2 and the C terminus, which contribute differentially towards the binding of the two G-protein subtypes, resulting in distinct CaSR-G-protein interfaces. The structures also reveal that natural polyamines target multiple sites on CaSR to enhance receptor activation by zipping negatively charged regions between two protomers. Furthermore, we find that the amino acid L-tryptophan, a well-known ligand of CaSR extracellular domains, occupies the 7TM bundle of the G-protein-coupled protomer at the same location as cinacalcet and other allosteric modulators. Together, these results provide a framework for G-protein activation and selectivity by CaSR, as well as its allosteric modulation by endogenous and exogenous ligands. | ||||||
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 | 8szg.cif.gz | 429.1 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb8szg.ent.gz | 327.5 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8szg.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 | 8szg_validation.pdf.gz | 1.5 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 8szg_full_validation.pdf.gz | 1.5 MB | 表示 | |
XML形式データ | 8szg_validation.xml.gz | 64.8 KB | 表示 | |
CIF形式データ | 8szg_validation.cif.gz | 97.7 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/sz/8szg ftp://data.pdbj.org/pub/pdb/validation_reports/sz/8szg | 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
-Guanine nucleotide-binding protein ... , 3種, 3分子 DEC
#1: タンパク質 | 分子量: 39885.484 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GNB1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P62873 |
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#2: タンパク質 | 分子量: 7861.143 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GNG2 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P59768 |
#5: タンパク質 | 分子量: 41353.078 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GNAQ, GAQ 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P50148 |
-Extracellular calcium-sensing ... , 2種, 2分子 AB
#3: タンパク質 | 分子量: 123820.969 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: CASR, GPRC2A, PCAR1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P41180 |
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#4: タンパク質 | 分子量: 108023.055 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: CASR, GPRC2A, PCAR1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P41180 |
-糖 , 2種, 7分子
#6: 多糖 | #8: 糖 | ChemComp-NAG / |
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-非ポリマー , 8種, 15分子
#7: 化合物 | #9: 化合物 | ChemComp-PCW / | #10: 化合物 | #11: 化合物 | #12: 化合物 | #13: 化合物 | #14: 化合物 | ChemComp-CLR / | #15: 水 | ChemComp-HOH / | |
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-詳細
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: Cinacalcet-bound human calcium-sensing receptor CaSR-Gq complex in lipid nanodiscs タイプ: COMPLEX / Entity ID: #1-#5 / 由来: RECOMBINANT |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
由来(組換発現) | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
緩衝液 | pH: 7.5 |
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): 1500 nm / 最小 デフォーカス(公称値): 500 nm |
撮影 | 電子線照射量: 50 e/Å2 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: 1.20.1_4487: / 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: 3.6 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 89192 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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