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基本情報
登録情報 | データベース: PDB / ID: 8jr9 | ||||||
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タイトル | Small molecule agonist (PCO371) bound to human parathyroid hormone receptor type 1 (PTH1R) | ||||||
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![]() | MEMBRANE PROTEIN / Class B / GPCR | ||||||
機能・相同性 | ![]() parathyroid hormone receptor activity / G protein-coupled peptide receptor activity / Class B/2 (Secretin family receptors) / osteoblast development / positive regulation of inositol phosphate biosynthetic process / bone mineralization / peptide hormone binding / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / cell maturation / chondrocyte differentiation ...parathyroid hormone receptor activity / G protein-coupled peptide receptor activity / Class B/2 (Secretin family receptors) / osteoblast development / positive regulation of inositol phosphate biosynthetic process / bone mineralization / peptide hormone binding / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / cell maturation / chondrocyte differentiation / bone resorption / skeletal system development / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / 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 / 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 / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / basolateral plasma membrane / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / in utero embryonic development / Extra-nuclear estrogen signaling / receptor complex / cell population proliferation / cell surface receptor signaling pathway / apical plasma membrane / G protein-coupled receptor signaling pathway / negative regulation of cell population proliferation / lysosomal membrane / GTPase activity / positive regulation of cell population proliferation / synapse / protein-containing complex binding / signal transduction / protein homodimerization activity / extracellular exosome / membrane / nucleus / plasma membrane / cytoplasm / cytosol 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: 2.57 Å | ||||||
![]() | Zhao, L. / He, Q. / Yuan, Q. / Gu, Y. / He, X. / Shan, H. / Li, J. / Wang, K. / Li, Y. / Hu, W. ...Zhao, L. / He, Q. / Yuan, Q. / Gu, Y. / He, X. / Shan, H. / Li, J. / Wang, K. / Li, Y. / Hu, W. / Wu, K. / Shen, J. / Xu, H.E. | ||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Conserved class B GPCR activation by a biased intracellular agonist. 著者: Li-Hua Zhao / Qian He / Qingning Yuan / Yimin Gu / Xinheng He / Hong Shan / Junrui Li / Kai Wang / Yang Li / Wen Hu / Kai Wu / Jianhua Shen / H Eric Xu / ![]() 要旨: Class B G-protein-coupled receptors (GPCRs), including glucagon-like peptide 1 receptor (GLP1R) and parathyroid hormone 1 receptor (PTH1R), are important drug targets. Injectable peptide drugs ...Class B G-protein-coupled receptors (GPCRs), including glucagon-like peptide 1 receptor (GLP1R) and parathyroid hormone 1 receptor (PTH1R), are important drug targets. Injectable peptide drugs targeting these receptors have been developed, but orally available small-molecule drugs remain under development. Here we report the high-resolution structure of human PTH1R in complex with the stimulatory G protein (G) and a small-molecule agonist, PCO371, which reveals an unexpected binding mode of PCO371 at the cytoplasmic interface of PTH1R with G. The PCO371-binding site is totally different from all binding sites previously reported for small molecules or peptide ligands in GPCRs. The residues that make up the PCO371-binding pocket are conserved in class B GPCRs, and a single alteration in PTH2R and two residue alterations in GLP1R convert these receptors to respond to PCO371. Functional assays reveal that PCO371 is a G-protein-biased agonist that is defective in promoting PTH1R-mediated arrestin signalling. Together, these results uncover a distinct binding site for designing small-molecule agonists for PTH1R and possibly other members of the class B GPCRs and define a receptor conformation that is specific only for G-protein activation but not arrestin signalling. These insights should facilitate the design of distinct types of class B GPCR small-molecule agonist for various therapeutic indications. | ||||||
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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ダウンロードとリンク
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ダウンロード
PDBx/mmCIF形式 | ![]() | 219.5 KB | 表示 | ![]() |
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PDB形式 | ![]() | 165.6 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
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-関連構造データ
関連構造データ | ![]() 36593MC 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 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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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
-Guanine nucleotide-binding protein ... , 3種, 3分子 ABG
#1: タンパク質 | 分子量: 41879.465 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() |
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#2: タンパク質 | 分子量: 38330.793 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: P62873 |
#3: 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) ![]() 発現宿主: ![]() ![]() 参照: UniProt: P59768 |
-抗体 / タンパク質 / 非ポリマー , 3種, 3分子 NR![](data/chem/img/KHF.gif)
![](data/chem/img/KHF.gif)
#4: 抗体 | 分子量: 15343.019 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() ![]() |
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#5: タンパク質 | 分子量: 54783.020 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: Q03431 |
#6: 化合物 | ChemComp-KHF / |
-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 |
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試料調製
構成要素 | 名称: A conserved and druggable pocket in class B G protein coupled receptors for 2 orally active small molecule agonists タイプ: COMPLEX / Entity ID: #1-#5 / 由来: MULTIPLE SOURCES |
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分子量 | 値: 0.16 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: 7.04 |
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 |
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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 / 最大 デフォーカス(公称値): 18000 nm / 最小 デフォーカス(公称値): 8000 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 (6k x 4k) |
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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: 2.57 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 1099315 / 対称性のタイプ: POINT |