- EMDB-24453: cryo-EM of human Glucagon-like peptide 1 receptor GLP-1R bound to... -
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データベース: EMDB / ID: EMD-24453
タイトル
cryo-EM of human Glucagon-like peptide 1 receptor GLP-1R bound to tirzepatide
マップデータ
試料
複合体: cryo-EM of human Glucagon-like peptide 1 receptor GLP-1R bound to tirzepatide, trimeric G protein complex and stabilizing antibodies
複合体: Glucagon-like peptide 1 receptor bound to tirzepatide
タンパク質・ペプチド: Tirzepatide
タンパク質・ペプチド: Glucagon-like peptide 1 receptor
複合体: Trimeric stimulatory G protein
タンパク質・ペプチド: Guanine nucleotide-binding protein G(i) subunit alpha-3,Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
タンパク質・ペプチド: 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(O) subunit gamma-2
タンパク質・ペプチド: Single-chain variable fragment 16
タンパク質・ペプチド: nanobody 35
機能・相同性
機能・相同性情報
glucagon-like peptide 1 receptor activity / glucagon receptor activity / hormone secretion / positive regulation of blood pressure / negative regulation of adenylate cyclase activity / post-translational protein targeting to membrane, translocation / GTP metabolic process / response to psychosocial stress / regulation of heart contraction / peptide hormone binding ...glucagon-like peptide 1 receptor activity / glucagon receptor activity / hormone secretion / positive regulation of blood pressure / negative regulation of adenylate cyclase activity / post-translational protein targeting to membrane, translocation / GTP metabolic process / response to psychosocial stress / regulation of heart contraction / peptide hormone binding / positive regulation of macroautophagy / PKA activation in glucagon signalling / hair follicle placode formation / developmental growth / D1 dopamine receptor binding / intracellular transport / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / Hedgehog 'off' state / Adenylate cyclase inhibitory pathway / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / negative regulation of blood pressure / regulation of insulin secretion / cellular response to glucagon stimulus / adenylate cyclase activator activity / trans-Golgi network membrane / negative regulation of inflammatory response to antigenic stimulus / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / bone development / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / centriolar satellite / platelet aggregation / cognition / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / GDP binding / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of smell / adenylate cyclase-activating dopamine receptor signaling pathway / transmembrane signaling receptor activity / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / positive regulation of cold-induced thermogenesis / G protein activity / positive regulation of cytosolic calcium ion concentration / GTPase binding / retina development in camera-type eye / Ca2+ pathway / midbody / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / 加水分解酵素; 酸無水物に作用; GTPに作用・細胞または細胞小器官の運動に関与 / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Ras protein signal transduction / learning or memory / Extra-nuclear estrogen signaling / cell population proliferation / cell surface receptor signaling pathway / ciliary basal body / G protein-coupled receptor signaling pathway / lysosomal membrane 類似検索 - 分子機能
GPCR, family 2, glucagon-like peptide-1 receptor / : / GPCR, family 2, glucagon-like peptide-1/glucagon 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 ...GPCR, family 2, glucagon-like peptide-1 receptor / : / GPCR, family 2, glucagon-like peptide-1/glucagon 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 / G-protein alpha subunit, group I / 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 / 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. / WD domain, G-beta repeat / 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) subunit alpha-3 / Glucagon-like peptide 1 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 類似検索 - 構成要素
生物種
Homo sapiens (ヒト) / Mus musculus (ハツカネズミ) / Lama glama (ラマ)
ジャーナル: Proc Natl Acad Sci U S A / 年: 2022 タイトル: Structural determinants of dual incretin receptor agonism by tirzepatide. 著者: Bingfa Sun / Francis S Willard / Dan Feng / Jorge Alsina-Fernandez / Qi Chen / Michal Vieth / Joseph D Ho / Aaron D Showalter / Cynthia Stutsman / Liyun Ding / Todd M Suter / James D Dunbar / ...著者: Bingfa Sun / Francis S Willard / Dan Feng / Jorge Alsina-Fernandez / Qi Chen / Michal Vieth / Joseph D Ho / Aaron D Showalter / Cynthia Stutsman / Liyun Ding / Todd M Suter / James D Dunbar / John W Carpenter / Faiz Ahmad Mohammed / Eitaro Aihara / Robert A Brown / Ana B Bueno / Paul J Emmerson / Julie S Moyers / Tong Sun Kobilka / Matthew P Coghlan / Brian K Kobilka / Kyle W Sloop / 要旨: SignificanceTirzepatide is a dual agonist of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R), which are incretin receptors that ...SignificanceTirzepatide is a dual agonist of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R), which are incretin receptors that regulate carbohydrate metabolism. This investigational agent has proven superior to selective GLP-1R agonists in clinical trials in subjects with type 2 diabetes mellitus. Intriguingly, although tirzepatide closely resembles native GIP in how it activates the GIPR, it differs markedly from GLP-1 in its activation of the GLP-1R, resulting in less agonist-induced receptor desensitization. We report how cryogenic electron microscopy and molecular dynamics simulations inform the structural basis for the unique pharmacology of tirzepatide. These studies reveal the extent to which fatty acid modification, combined with amino acid sequence, determines the mode of action of a multireceptor agonist.
全体 : cryo-EM of human Glucagon-like peptide 1 receptor GLP-1R bound to...
全体
名称: cryo-EM of human Glucagon-like peptide 1 receptor GLP-1R bound to tirzepatide, trimeric G protein complex and stabilizing antibodies
要素
複合体: cryo-EM of human Glucagon-like peptide 1 receptor GLP-1R bound to tirzepatide, trimeric G protein complex and stabilizing antibodies
複合体: Glucagon-like peptide 1 receptor bound to tirzepatide
タンパク質・ペプチド: Tirzepatide
タンパク質・ペプチド: Glucagon-like peptide 1 receptor
複合体: Trimeric stimulatory G protein
タンパク質・ペプチド: Guanine nucleotide-binding protein G(i) subunit alpha-3,Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
タンパク質・ペプチド: 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(O) subunit gamma-2
タンパク質・ペプチド: Single-chain variable fragment 16
タンパク質・ペプチド: nanobody 35
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超分子 #1: cryo-EM of human Glucagon-like peptide 1 receptor GLP-1R bound to...
超分子
名称: cryo-EM of human Glucagon-like peptide 1 receptor GLP-1R bound to tirzepatide, trimeric G protein complex and stabilizing antibodies タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: all
分子量
理論値: 150 KDa
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超分子 #2: Glucagon-like peptide 1 receptor bound to tirzepatide