登録情報 データベース : PDB / ID : 8itl 構造の表示 ダウンロードとリンクタイトル Cryo-EM structure of GIPR splice variant 1 (SV1) in complex with Gs protein 要素Gastric inhibitory polypeptide receptor Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 Guanine nucleotide-binding protein G(s) subunit alpha isoforms short Nanobody-35 ナノボディ 詳細キーワード STRUCTURAL PROTEIN (タンパク質) / Cryo-electron microscopy (低温電子顕微鏡法) / G protein-coupled receptor (Gタンパク質共役受容体) / splice variant / receptor activation. (受容体)機能・相同性 機能・相同性情報分子機能 ドメイン・相同性 構成要素
gastric inhibitory peptide receptor activity / glucagon family peptide binding / gastric inhibitory peptide signaling pathway / desensitization of G protein-coupled receptor signaling pathway / sensory perception of chemical stimulus / endocrine pancreas development / response to fatty acid / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / G-protein activation ... gastric inhibitory peptide receptor activity / glucagon family peptide binding / gastric inhibitory peptide signaling pathway / desensitization of G protein-coupled receptor signaling pathway / sensory perception of chemical stimulus / endocrine pancreas development / response to fatty acid / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / 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 / 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 / alkylglycerophosphoethanolamine phosphodiesterase activity / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / 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 / G alpha (s) signalling events / beta-2 adrenergic receptor binding / G alpha (q) signalling events / 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 / peptide hormone binding / regulation of insulin secretion / positive regulation of cAMP-mediated signaling / photoreceptor outer segment / response to axon injury / D1 dopamine receptor binding / response to glucose / adenylate cyclase-activating adrenergic receptor signaling pathway / cardiac muscle cell apoptotic process / insulin-like growth factor receptor binding / ionotropic glutamate receptor binding / activation of adenylate cyclase activity / adenylate cyclase activator activity / photoreceptor inner segment / response to nutrient / generation of precursor metabolites and energy / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / positive regulation of insulin secretion / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Glucagon-type ligand receptors / cellular response to catecholamine stimulus / response to calcium ion / sensory perception of taste / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / transmembrane signaling receptor activity / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / cell body / positive regulation of cytosolic calcium ion concentration / cellular response to hypoxia / G alpha (s) signalling events / cell population proliferation / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / GTPase activity / 樹状突起 類似検索 - 分子機能 GPCR, family 2, gastric inhibitory polypeptide receptor / G-protein coupled receptors family 2 signature 1. / Hormone receptor domain / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / GPCR family 2, extracellular hormone receptor domain superfamily / G-protein coupled receptors family 2 signature 2. / GPCR, family 2, secretin-like, conserved site / GPCR, family 2, secretin-like ... GPCR, family 2, gastric inhibitory polypeptide receptor / G-protein coupled receptors family 2 signature 1. / Hormone receptor domain / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / GPCR family 2, extracellular hormone receptor domain superfamily / G-protein coupled receptors family 2 signature 2. / GPCR, family 2, secretin-like, conserved site / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / G-protein alpha subunit, group S / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40リピート / WD40リピート / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase 類似検索 - ドメイン・相同性 Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Gastric inhibitory polypeptide receptor / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 類似検索 - 構成要素生物種 Homo sapiens (ヒト)Bos taurus (ウシ)Rattus norvegicus (ドブネズミ)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 : 3.23 Å 詳細データ登録者 Zhao, F.H. / Hang, K.N. / Zhou, Q.T. / Shao, L.J. / Li, H. / Li, W.Z. / Lin, S. / Dai, A.T. / Cai, X.Q. / Liu, Y.Y. ...Zhao, F.H. / Hang, K.N. / Zhou, Q.T. / Shao, L.J. / Li, H. / Li, W.Z. / Lin, S. / Dai, A.T. / Cai, X.Q. / Liu, Y.Y. / Xu, Y.N. / Feng, W.B. / Yang, D.H. / Wang, M.W. 資金援助 中国, 6件 詳細 詳細を隠す組織 認可番号 国 National Natural Science Foundation of China (NSFC) 81872915 中国 National Natural Science Foundation of China (NSFC) 82073904 中国 National Natural Science Foundation of China (NSFC) 82121005 中国 National Natural Science Foundation of China (NSFC) 81973373 中国 National Natural Science Foundation of China (NSFC) 21704064 中国 National Natural Science Foundation of China (NSFC) 82204474 中国
引用ジャーナル : Proc Natl Acad Sci U S A / 年 : 2023タイトル : Molecular basis of signal transduction mediated by the human GIPR splice variants.著者 : Fenghui Zhao / Kaini Hang / Qingtong Zhou / Lijun Shao / Hao Li / Wenzhuo Li / Shi Lin / Antao Dai / Xiaoqing Cai / Yanyun Liu / Yingna Xu / Wenbo Feng / Dehua Yang / Ming-Wei Wang / 要旨 : Glucose-dependent insulinotropic polypeptide receptor (GIPR) is a potential drug target for metabolic disorders. It works with glucagon-like peptide-1 receptor and glucagon receptor in humans to ... Glucose-dependent insulinotropic polypeptide receptor (GIPR) is a potential drug target for metabolic disorders. It works with glucagon-like peptide-1 receptor and glucagon receptor in humans to maintain glucose homeostasis. Unlike the other two receptors, GIPR has at least 13 reported splice variants (SVs), more than half of which have sequence variations at either C or N terminus. To explore their roles in endogenous peptide-mediated GIPR signaling, we determined the cryoelectron microscopy (cryo-EM) structures of the two N terminus-altered SVs (referred as GIPR-202 and GIPR-209 in the Ensembl database, SV1 and SV2 here, respectively) and investigated the outcome of coexpressing each of them in question with GIPR in HEK293T cells with respect to ligand binding, receptor expression, cAMP (adenosine 3,5-cyclic monophosphate) accumulation, β-arrestin recruitment, and cell surface localization. It was found that while both N terminus-altered SVs of GIPR neither bound to the hormone nor elicited signal transduction per se, they suppressed ligand binding and cAMP accumulation of GIPR. Meanwhile, SV1 reduced GIPR-mediated β-arrestin 2 responses. The cryo-EM structures of SV1 and SV2 showed that they reorganized the extracellular halves of transmembrane helices 1, 6, and 7 and extracellular loops 2 and 3 to adopt a ligand-binding pocket-occupied conformation, thereby losing binding ability to the peptide. The results suggest a form of signal bias that is constitutive and ligand-independent, thus expanding our knowledge of biased signaling beyond pharmacological manipulation (i.e., ligand specific) as well as constitutive and ligand-independent (e.g., SV1 of the growth hormone-releasing hormone receptor). 履歴 登録 2023年3月22日 登録サイト : PDBJ / 処理サイト : PDBC改定 1.0 2023年10月18日 Provider : repository / タイプ : Initial release