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基本情報
登録情報 | データベース: PDB / ID: 7cz5 | ||||||
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タイトル | Cryo-EM structure of the human growth hormone-releasing hormone receptor-Gs protein complex | ||||||
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![]() | MEMBRANE PROTEIN / cognate receptor / Class B G-protein-coupled receptors / single particle | ||||||
機能・相同性 | ![]() regulation of intracellular steroid hormone receptor signaling pathway / somatotropin secreting cell development / growth hormone-releasing hormone receptor binding / positive regulation of circadian sleep/wake cycle, REM sleep / growth hormone-releasing hormone receptor activity / growth hormone-releasing hormone activity / growth hormone secretion / adenohypophysis development / positive regulation of growth hormone secretion / regulation of protein metabolic process ...regulation of intracellular steroid hormone receptor signaling pathway / somatotropin secreting cell development / growth hormone-releasing hormone receptor binding / positive regulation of circadian sleep/wake cycle, REM sleep / growth hormone-releasing hormone receptor activity / growth hormone-releasing hormone activity / growth hormone secretion / adenohypophysis development / positive regulation of growth hormone secretion / regulation of protein metabolic process / positive regulation of multicellular organism growth / multicellular organismal reproductive process / neuropeptide hormone activity / 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 protein-coupled peptide receptor activity / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / hormone metabolic process / nuclear outer membrane / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / G alpha (i) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / 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 / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / alkylglycerophosphoethanolamine phosphodiesterase activity / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / positive regulation of insulin-like growth factor receptor signaling pathway / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / nuclear inner membrane / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / response to food / G alpha (q) signalling events / peptide hormone receptor binding / photoreceptor outer segment membrane / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / growth factor binding / peptide hormone binding / PKA activation in glucagon signalling / hair follicle placode formation / mu-type opioid receptor binding / photoreceptor outer segment / developmental growth / corticotropin-releasing hormone receptor 1 binding / intracellular transport / D1 dopamine receptor binding / Hedgehog 'off' state / beta-2 adrenergic receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / response to glucocorticoid / cell maturation / cardiac muscle cell apoptotic process / activation of adenylate cyclase activity / adenylate cyclase activator activity / lactation / photoreceptor inner segment / trans-Golgi network membrane / secretory granule / establishment of localization in cell / G protein-coupled receptor activity / determination of adult lifespan / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / G-protein beta/gamma-subunit complex binding / bone development / response to insulin / multicellular organism growth / adenylate cyclase-activating G protein-coupled receptor signaling pathway / terminal bouton 類似検索 - 分子機能 | ||||||
生物種 | ![]() ![]() ![]() ![]() ![]() synthetic construct (人工物) | ||||||
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: 2.6 Å | ||||||
![]() | Zhou, F. / Zhang, H. / Cong, Z. / Zhao, L. / Zhou, Q. / Mao, C. / Cheng, X. / Shen, D. / Cai, X. / Ma, C. ...Zhou, F. / Zhang, H. / Cong, Z. / Zhao, L. / Zhou, Q. / Mao, C. / Cheng, X. / Shen, D. / Cai, X. / Ma, C. / Wang, Y. / Dai, A. / Zhou, Y. / Sun, W. / Zhao, F. / Zhao, S. / Jiang, H. / Jiang, Y. / Yang, D. / Xu, H.E. / Zhang, Y. / Wang, M. | ||||||
![]() | ![]() タイトル: Structural basis for activation of the growth hormone-releasing hormone receptor. 著者: Fulai Zhou / Huibing Zhang / Zhaotong Cong / Li-Hua Zhao / Qingtong Zhou / Chunyou Mao / Xi Cheng / Dan-Dan Shen / Xiaoqing Cai / Cheng Ma / Yuzhe Wang / Antao Dai / Yan Zhou / Wen Sun / ...著者: Fulai Zhou / Huibing Zhang / Zhaotong Cong / Li-Hua Zhao / Qingtong Zhou / Chunyou Mao / Xi Cheng / Dan-Dan Shen / Xiaoqing Cai / Cheng Ma / Yuzhe Wang / Antao Dai / Yan Zhou / Wen Sun / Fenghui Zhao / Suwen Zhao / Hualiang Jiang / Yi Jiang / Dehua Yang / H Eric Xu / Yan Zhang / Ming-Wei Wang / ![]() 要旨: Growth hormone-releasing hormone (GHRH) regulates the secretion of growth hormone that virtually controls metabolism and growth of every tissue through its binding to the cognate receptor (GHRHR). ...Growth hormone-releasing hormone (GHRH) regulates the secretion of growth hormone that virtually controls metabolism and growth of every tissue through its binding to the cognate receptor (GHRHR). Malfunction in GHRHR signaling is associated with abnormal growth, making GHRHR an attractive therapeutic target against dwarfism (e.g., isolated growth hormone deficiency, IGHD), gigantism, lipodystrophy and certain cancers. Here, we report the cryo-electron microscopy (cryo-EM) structure of the human GHRHR bound to its endogenous ligand and the stimulatory G protein at 2.6 Å. This high-resolution structure reveals a characteristic hormone recognition pattern of GHRH by GHRHR, where the α-helical GHRH forms an extensive and continuous network of interactions involving all the extracellular loops (ECLs), all the transmembrane (TM) helices except TM4, and the extracellular domain (ECD) of GHRHR, especially the N-terminus of GHRH that engages a broad set of specific interactions with the receptor. Mutagenesis and molecular dynamics (MD) simulations uncover detailed mechanisms by which IGHD-causing mutations lead to the impairment of GHRHR function. Our findings provide insights into the molecular basis of peptide recognition and receptor activation, thereby facilitating the development of structure-based drug discovery and precision medicine. | ||||||
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構造ビューア | 分子: ![]() ![]() |
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PDBx/mmCIF形式 | ![]() | 204.9 KB | 表示 | ![]() |
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PDB形式 | ![]() | 160.5 KB | 表示 | ![]() |
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-検証レポート
文書・要旨 | ![]() | 975.8 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 996.3 KB | 表示 | |
XML形式データ | ![]() | 33.8 KB | 表示 | |
CIF形式データ | ![]() | 50.7 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
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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
-タンパク質 , 2種, 2分子 RN
#1: タンパク質 | 分子量: 61651.438 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: Q02643 |
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#6: タンパク質 | 分子量: 13711.284 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) synthetic construct (人工物) / 発現宿主: ![]() ![]() |
-Guanine nucleotide-binding protein ... , 3種, 3分子 ABG
#2: タンパク質 | 分子量: 45683.434 Da / 分子数: 1 Mutation: S54N, G226A, E268A, N271K, K274D, R280K, T284D, I285T 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: P63092 |
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#4: タンパク質 | 分子量: 43706.750 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: P54311 |
#5: 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: P63212 |
-タンパク質・ペプチド , 1種, 1分子 P
#3: タンパク質・ペプチド | 分子量: 5048.702 Da / 分子数: 1 / 由来タイプ: 合成 / 由来: (合成) ![]() |
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-非ポリマー , 3種, 6分子 ![](data/chem/img/PLM.gif)
![](data/chem/img/CLR.gif)
![](data/chem/img/HOH.gif)
![](data/chem/img/CLR.gif)
![](data/chem/img/HOH.gif)
#7: 化合物 | #8: 化合物 | ChemComp-CLR / | #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 | N |
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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 |
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分子量 | 値: 0.18 MDa / 実験値: YES | |||||||||||||||||||||||||||||||||||||||||||||||||
由来(天然) |
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由来(組換発現) |
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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 |
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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 |
撮影 | 電子線照射量: 62 e/Å2 / 検出モード: COUNTING フィルム・検出器のモデル: GATAN K2 QUANTUM (4k x 4k) |
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解析
ソフトウェア | 名称: PHENIX / バージョン: 1.16_3549: / 分類: 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: 2.6 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 307018 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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