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基本情報
登録情報 | データベース: PDB / ID: 7fee | ||||||
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タイトル | Crystal structure of the allosteric modulator ZCZ011 binding to CP55940-bound cannabinoid receptor 1 | ||||||
![]() | Cannabinoid receptor 1,GlgA glycogen synthase | ||||||
![]() | MEMBRANE PROTEIN / signal protein / GPCR | ||||||
機能・相同性 | ![]() cannabinoid signaling pathway / regulation of penile erection / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / negative regulation of mast cell activation / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity / negative regulation of fatty acid beta-oxidation / negative regulation of dopamine secretion / positive regulation of acute inflammatory response to antigenic stimulus ...cannabinoid signaling pathway / regulation of penile erection / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / negative regulation of mast cell activation / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity / negative regulation of fatty acid beta-oxidation / negative regulation of dopamine secretion / positive regulation of acute inflammatory response to antigenic stimulus / negative regulation of serotonin secretion / regulation of feeding behavior / regulation of presynaptic cytosolic calcium ion concentration / negative regulation of action potential / Class A/1 (Rhodopsin-like receptors) / positive regulation of blood pressure / positive regulation of fever generation / regulation of metabolic process / axonal fasciculation / glycogen biosynthetic process / regulation of synaptic transmission, GABAergic / regulation of insulin secretion / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / GABA-ergic synapse / maternal process involved in female pregnancy / regulation of synaptic transmission, glutamatergic / negative regulation of blood pressure / response to nutrient / response to cocaine / G protein-coupled receptor activity / response to nicotine / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / memory / positive regulation of neuron projection development / actin cytoskeleton / glucose homeostasis / presynaptic membrane / G alpha (i) signalling events / growth cone / spermatogenesis / response to ethanol / mitochondrial outer membrane / response to lipopolysaccharide / positive regulation of apoptotic process / membrane raft / glutamatergic synapse / identical protein binding / plasma membrane / cytosol / cytoplasm 類似検索 - 分子機能 | ||||||
生物種 | ![]() ![]() ![]() | ||||||
手法 | ![]() ![]() ![]() | ||||||
![]() | Wang, X. / Zhao, C. / Shao, Z. | ||||||
資金援助 | 1件
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![]() | ![]() タイトル: Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1. 著者: Xin Yang / Xuehui Wang / Zheng Xu / Chao Wu / Yangli Zhou / Yifei Wang / Guifeng Lin / Kan Li / Ming Wu / Anjie Xia / Jingming Liu / Lin Cheng / Jun Zou / Wei Yan / Zhenhua Shao / Shengyong Yang / ![]() 要旨: Given the promising clinical value of allosteric modulators of G protein-coupled-receptors (GPCRs), mechanistic understanding of how these modulators alter GPCR function is of significance. Here, we ...Given the promising clinical value of allosteric modulators of G protein-coupled-receptors (GPCRs), mechanistic understanding of how these modulators alter GPCR function is of significance. Here, we report the crystallographic and cryo-electron microscopy structures of the cannabinoid receptor CB1 bound to the positive allosteric modulator (PAM) ZCZ011. These structures show that ZCZ011 binds to an extrahelical site in the transmembrane 2 (TM2)-TM3-TM4 surface. Through (un)biased molecular dynamics simulations and mutagenesis experiments, we show that TM2 rearrangement is critical for the propagation of allosteric signals. ZCZ011 exerts a PAM effect by promoting TM2 rearrangement in favor of receptor activation and increasing the population of receptors that adopt an active conformation. In contrast, ORG27569, a negative allosteric modulator (NAM) of CB1, also binds to the TM2-TM3-TM4 surface and exerts a NAM effect by impeding the TM2 rearrangement. Our findings fill a gap in the understanding of CB1 allosteric regulation and could guide the rational design of CB1 allosteric modulators. | ||||||
履歴 |
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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PDBx/mmCIF形式 | ![]() | 224.9 KB | 表示 | ![]() |
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PDB形式 | ![]() | 178.2 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 | ![]() 7wv9C ![]() 5u09S S: 精密化の開始モデル 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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単位格子 |
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要素
-タンパク質 , 1種, 1分子 A
#1: タンパク質 | 分子量: 63564.348 Da / 分子数: 1 / 変異: S203K,T210A,E273K,T283V,R340E,N393D / 由来タイプ: 組換発現 詳細: Cannabinoid receptor 1 inserted with GlgA glycogen synthase 由来: (組換発現) ![]() ![]() ![]() 遺伝子: CNR1, CNR, PAB2292 / プラスミド: PFASTbac / 細胞株 (発現宿主): Sf9 発現宿主: ![]() ![]() 参照: UniProt: P21554, UniProt: Q9V2J8 |
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-非ポリマー , 8種, 34分子 ![](data/chem/img/CLR.gif)
![](data/chem/img/9GF.gif)
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![](data/chem/img/PEG.gif)
![](data/chem/img/GOL.gif)
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![](data/chem/img/HOH.gif)
![](data/chem/img/9GF.gif)
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![](data/chem/img/GOL.gif)
![](data/chem/img/OLC.gif)
![](data/chem/img/OLA.gif)
![](data/chem/img/HOH.gif)
#2: 化合物 | #3: 化合物 | ChemComp-9GF / | #4: 化合物 | ChemComp-7IC / | #5: 化合物 | #6: 化合物 | ChemComp-GOL / #7: 化合物 | #8: 化合物 | ChemComp-OLA / #9: 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: ![]() |
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試料調製
結晶 | マシュー密度: 2.72 Å3/Da / 溶媒含有率: 54.78 % |
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結晶化 | 温度: 293 K / 手法: 脂質キュービック相法 / pH: 6 詳細: 25-36% PEG 300, 100Mm MES pH 6.0, 120-190mM Magnesium Sulfate |
-データ収集
回折 | 平均測定温度: 100 K / Serial crystal experiment: N |
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放射光源 | 由来: ![]() ![]() ![]() |
検出器 | タイプ: DECTRIS EIGER X 16M / 検出器: PIXEL / 日付: 2020年10月20日 |
放射 | プロトコル: SINGLE WAVELENGTH / 単色(M)・ラウエ(L): M / 散乱光タイプ: x-ray |
放射波長 | 波長: 1 Å / 相対比: 1 |
反射 | 解像度: 2.7→42.6 Å / Num. obs: 17318 / 冗長度: 32.7 % / Biso Wilson estimate: 86.93 Å2 / CC1/2: 0.987 / Net I/σ(I): 12.6 |
反射 シェル | 解像度: 2.7→2.79 Å / Num. unique obs: 1694 / CC1/2: 0.733 |
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解析
ソフトウェア |
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精密化 | 構造決定の手法: ![]() 開始モデル: 5u09 解像度: 2.7→42.6 Å / SU ML: 0.52 / 交差検証法: THROUGHOUT / σ(F): 1.33 / 位相誤差: 38.83 / 立体化学のターゲット値: ML
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溶媒の処理 | 減衰半径: 0.9 Å / VDWプローブ半径: 1.11 Å / 溶媒モデル: FLAT BULK SOLVENT MODEL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
原子変位パラメータ | Biso max: 192.18 Å2 / Biso mean: 107.2729 Å2 / Biso min: 61.05 Å2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
精密化ステップ | サイクル: final / 解像度: 2.7→42.6 Å
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LS精密化 シェル | Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11
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精密化 TLS | 手法: refined / Origin x: 9.5811 Å / Origin y: 14.486 Å / Origin z: 18.5805 Å
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精密化 TLSグループ |
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