+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 9ijd | ||||||
---|---|---|---|---|---|---|---|
タイトル | Carazolol-activated human beta3 adrenergic receptor | ||||||
要素 |
| ||||||
キーワード | MEMBRANE PROTEIN/IMMUNE SYSTEM / Complex / beta3AR / MEMBRANE PROTEIN-IMMUNE SYSTEM complex | ||||||
機能・相同性 | 機能・相同性情報 beta-3 adrenergic receptor binding / beta3-adrenergic receptor activity / beta-adrenergic receptor activity / epinephrine binding / sensory perception of chemical stimulus / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / energy reserve metabolic process / G-protein activation / Activation of the phototransduction cascade ...beta-3 adrenergic receptor binding / beta3-adrenergic receptor activity / beta-adrenergic receptor activity / epinephrine binding / sensory perception of chemical stimulus / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / energy reserve metabolic process / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (i) signalling events / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / norepinephrine binding / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / alkylglycerophosphoethanolamine phosphodiesterase activity / Adrenoceptors / heat generation / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / G alpha (z) signalling events / Extra-nuclear estrogen signaling / beta-2 adrenergic receptor binding / G alpha (s) signalling events / G alpha (q) signalling events / photoreceptor outer segment membrane / G alpha (i) signalling events / negative regulation of multicellular organism growth / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / eating behavior / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / diet induced thermogenesis / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / photoreceptor outer segment / D1 dopamine receptor binding / generation of precursor metabolites and energy / adenylate cyclase-activating adrenergic receptor signaling pathway / brown fat cell differentiation / cardiac muscle cell apoptotic process / insulin-like growth factor receptor binding / adenylate cyclase activator activity / ionotropic glutamate receptor binding / photoreceptor inner segment / response to cold / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / cellular response to catecholamine stimulus / sensory perception of taste / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / GTPase binding / retina development in camera-type eye / cellular response to hypoxia / positive regulation of cold-induced thermogenesis / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / cell body / G alpha (s) signalling events / receptor complex / cell population proliferation / positive regulation of MAPK cascade / carbohydrate metabolic process / G protein-coupled receptor signaling pathway / GTPase activity / dendrite 類似検索 - 分子機能 | ||||||
生物種 | Rattus norvegicus (ドブネズミ) Lama glama (ラマ) Homo sapiens (ヒト) Bos taurus (ウシ) | ||||||
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: 2.76 Å | ||||||
データ登録者 | Zheng, S. / Zhang, S. / Dai, S. / Chen, K. / Gao, K. / Lin, B. / Liu, X. | ||||||
資金援助 | 中国, 1件
| ||||||
引用 | ジャーナル: Chempluschem / 年: 2024 タイトル: Molecular Mechanism of the β3AR Agonist Activity of a β-Blocker. 著者: Shuang Zheng / Shuhao Zhang / Shengjie Dai / Kai Chen / Kaixuan Gao / Xiaoou Sun / Bin Lin / Xiangyu Liu / 要旨: Development of subtype-selective drugs for G protein-coupled receptors poses a significant challenge due to high similarity between subtypes, as exemplified by the three β-adrenergic receptors ...Development of subtype-selective drugs for G protein-coupled receptors poses a significant challenge due to high similarity between subtypes, as exemplified by the three β-adrenergic receptors (βARs). The β3AR agonists show promise for treating the overactive bladder or preterm birth, but their potential is hindered by off-target activation of β1AR and β2AR. Interestingly, several β-blockers, which are antagonists of the β1ARs and β2ARs, have been reported to exhibit agonist activity at the β3AR. However, the molecular mechanism remains elusive. Understanding the underlying mechanism should facilitate the development of β3AR agonist drugs with improved selectivity and reduced off-target effects. In this work, we determined the structures of human β3AR in complex with the endogenous agonist epinephrine or with a synthetic β3AR agonist carazolol, which is also a high-affinity β-blocker. Structure comparison, mutagenesis studies and molecular dynamics simulations revealed that the differences on the flexibility of D3.32 directly contribute to carazolol's distinct activities as an antagonist for the β2AR and an agonist for the β3AR. The process is also indirectly influenced by the extracellular loops (ECL), especially ECL1. Taken together, these results provide key guidance for development of selective β3AR agonists, paving the way for new therapeutic opportunities. | ||||||
履歴 |
|
-構造の表示
構造ビューア | 分子: MolmilJmol/JSmol |
---|
-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 9ijd.cif.gz | 251.4 KB | 表示 | PDBx/mmCIF形式 |
---|---|---|---|---|
PDB形式 | pdb9ijd.ent.gz | 193.5 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 9ijd.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
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/ij/9ijd ftp://data.pdbj.org/pub/pdb/validation_reports/ij/9ijd | HTTPS FTP |
---|
-関連構造データ
関連構造データ | 60628MC 9ijeC 39846 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 (文献) |
---|---|
類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-リンク
-集合体
登録構造単位 |
|
---|---|
1 |
|
-要素
-Guanine nucleotide-binding protein ... , 3種, 3分子 BAC
#1: タンパク質 | 分子量: 37413.863 Da / 分子数: 1 / 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: Gnb1 / 発現宿主: Trichoplusia ni (イラクサキンウワバ) / 参照: UniProt: P54311 |
---|---|
#5: タンパク質 | 分子量: 43320.797 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Bos taurus (ウシ) / 遺伝子: GNAS, GNAS1 / 発現宿主: Trichoplusia ni (イラクサキンウワバ) / 参照: UniProt: P04896 |
#6: タンパク質 | 分子量: 5731.619 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Bos taurus (ウシ) / 遺伝子: GNG2 / 発現宿主: Trichoplusia ni (イラクサキンウワバ) / 参照: UniProt: P63212 |
-抗体 , 2種, 2分子 ND
#2: 抗体 | 分子量: 13885.439 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Lama glama (ラマ) / 発現宿主: Escherichia coli (大腸菌) |
---|---|
#3: 抗体 | 分子量: 26206.219 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 発現宿主: Trichoplusia ni (イラクサキンウワバ) |
-タンパク質 / 非ポリマー , 2種, 2分子 R
#4: タンパク質 | 分子量: 34647.020 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: ADRB3, ADRB3R, B3AR / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: P13945 |
---|---|
#7: 化合物 | ChemComp-CAU / ( |
-詳細
研究の焦点であるリガンドがあるか | Y |
---|
-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
---|---|
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: Carazolol bounded human beta3 adrenergic receptor-Gs protein complex with Gbeta, Ggamma, Nb35 and scFv16 タイプ: COMPLEX / Entity ID: #1-#6 / 由来: MULTIPLE SOURCES |
---|---|
由来(天然) | 生物種: Homo sapiens (ヒト) |
由来(組換発現) | 生物種: Homo sapiens (ヒト) |
緩衝液 | pH: 8 |
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
顕微鏡 | モデル: FEI TITAN |
---|---|
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): 1100 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) |
-解析
CTF補正 | タイプ: NONE | ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
3次元再構成 | 解像度: 2.76 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 1623386 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
|