登録情報 データベース : EMDB / ID : EMD-34305 ダウンロードとリンクタイトル the human PTH1 receptor bound to an intracellular biased agonist マップデータ 詳細 試料複合体 : the human PTH1 receptor bound to an intracellular biased agonist複合体 : Guanine nucleotide-binding protein G(s) subunit alpha isoforms shortタンパク質・ペプチド : Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short複合体 : Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1タンパク質・ペプチド : Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1複合体 : Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2タンパク質・ペプチド : Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2複合体 : nanobody Nb35複合体 : Parathyroid hormone/parathyroid hormone-related peptide receptorタンパク質・ペプチド : Parathyroid hormone/parathyroid hormone-related peptide receptorリガンド : PCO-371 詳細 キーワード G protein-coupled receptor / membrane protein / SIGNALING PROTEIN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
parathyroid hormone receptor 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 ... parathyroid hormone receptor 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 alpha (z) signalling events / Class B/2 (Secretin family receptors) / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G protein-coupled peptide receptor activity / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / osteoblast development / 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 / G alpha (12/13) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Ca2+ pathway / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (z) signalling events / Extra-nuclear estrogen signaling / photoreceptor outer segment membrane / G alpha (s) signalling events / positive regulation of inositol phosphate biosynthetic process / G alpha (q) signalling events / spectrin binding / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / bone mineralization / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / alkylglycerophosphoethanolamine phosphodiesterase activity / peptide hormone binding / PKA activation in glucagon signalling / developmental growth / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / hair follicle placode formation / photoreceptor outer segment / chondrocyte differentiation / D1 dopamine receptor binding / bone resorption / intracellular transport / vascular endothelial cell response to laminar fluid shear stress / activation of adenylate cyclase activity / renal water homeostasis / cell maturation / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / photoreceptor inner segment / cardiac muscle cell apoptotic process / cellular response to glucagon stimulus / regulation of insulin secretion / adenylate cyclase activator activity / trans-Golgi network membrane / skeletal system development / negative regulation of inflammatory response to antigenic stimulus / bone development / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / platelet aggregation / G-protein beta/gamma-subunit complex binding / cognition / intracellular calcium ion homeostasis / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of smell / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex 類似検索 - 分子機能 GPCR, family 2, parathyroid hormone receptor / G-protein coupled receptors family 2 signature 1. / : / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / Hormone receptor domain / 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, parathyroid hormone receptor / G-protein coupled receptors family 2 signature 1. / : / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / Hormone receptor domain / 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 / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / 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. / WD40 repeats / WD40 repeat / 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(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Parathyroid hormone/parathyroid hormone-related peptide receptor 類似検索 - 構成要素生物種 Homo sapiens (ヒト) / Rattus norvegicus (ドブネズミ) / Bos taurus (ウシ) / unidentified (未定義) 手法 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度 : 2.9 Å 詳細 データ登録者Kobayashi K / Kusakizako T / Okamoto HH / Nureki O / Yamashita K / Nishizawa T / Kato HE 資金援助 日本, 1件 詳細 詳細を隠すOrganization Grant number 国 Japan Society for the Promotion of Science (JSPS) 日本
引用ジャーナル : Nature / 年 : 2023タイトル : Class B1 GPCR activation by an intracellular agonist.著者: Kazuhiro Kobayashi / Kouki Kawakami / Tsukasa Kusakizako / Atsuhiro Tomita / Michihiro Nishimura / Kazuhiro Sawada / Hiroyuki H Okamoto / Suzune Hiratsuka / Gaku Nakamura / Riku Kuwabara / ... 著者 : Kazuhiro Kobayashi / Kouki Kawakami / Tsukasa Kusakizako / Atsuhiro Tomita / Michihiro Nishimura / Kazuhiro Sawada / Hiroyuki H Okamoto / Suzune Hiratsuka / Gaku Nakamura / Riku Kuwabara / Hiroshi Noda / Hiroyasu Muramatsu / Masaru Shimizu / Tomohiko Taguchi / Asuka Inoue / Takeshi Murata / Osamu Nureki / 要旨 : G protein-coupled receptors (GPCRs) generally accommodate specific ligands in the orthosteric-binding pockets. Ligand binding triggers a receptor allosteric conformational change that leads to the ... G protein-coupled receptors (GPCRs) generally accommodate specific ligands in the orthosteric-binding pockets. Ligand binding triggers a receptor allosteric conformational change that leads to the activation of intracellular transducers, G proteins and β-arrestins. Because these signals often induce adverse effects, the selective activation mechanism for each transducer must be elucidated. Thus, many orthosteric-biased agonists have been developed, and intracellular-biased agonists have recently attracted broad interest. These agonists bind within the receptor intracellular cavity and preferentially tune the specific signalling pathway over other signalling pathways, without allosteric rearrangement of the receptor from the extracellular side. However, only antagonist-bound structures are currently available, and there is no evidence to support that biased agonist binding occurs within the intracellular cavity. This limits the comprehension of intracellular-biased agonism and potential drug development. Here we report the cryogenic electron microscopy structure of a complex of G and the human parathyroid hormone type 1 receptor (PTH1R) bound to a PTH1R agonist, PCO371. PCO371 binds within an intracellular pocket of PTH1R and directly interacts with G. The PCO371-binding mode rearranges the intracellular region towards the active conformation without extracellularly induced allosteric signal propagation. PCO371 stabilizes the significantly outward-bent conformation of transmembrane helix 6, which facilitates binding to G proteins rather than β-arrestins. Furthermore, PCO371 binds within the highly conserved intracellular pocket, activating 7 out of the 15 class B1 GPCRs. Our study identifies a new and conserved intracellular agonist-binding pocket and provides evidence of a biased signalling mechanism that targets the receptor-transducer interface. 履歴 登録 2022年9月16日 - ヘッダ(付随情報) 公開 2023年6月14日 - マップ公開 2023年6月14日 - 更新 2025年7月2日 - 現状 2025年7月2日 処理サイト : PDBj / 状態 : 公開
すべて表示 表示を減らす