- EMDB-40915: Cryo-EM structure of cinacalcet-bound human calcium-sensing recep... -
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データベース: EMDB / ID: EMD-40915
タイトル
Cryo-EM structure of cinacalcet-bound human calcium-sensing receptor CaSR-Gq complex in lipid nanodiscs
マップデータ
試料
複合体: Cinacalcet-bound human calcium-sensing receptor CaSR-Gq complex in lipid nanodiscs
タンパク質・ペプチド: x 5種
リガンド: x 9種
キーワード
Family C GPCR / Calcium-sensing Receptor (CaSR) / Heterotrimeric G protein / Cryo-EM / Lipid Nanodiscs / Positive Allosteric Modulator / Membrane Protein / SIGNALING PROTEIN
機能・相同性
機能・相同性情報
Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / bile acid secretion / Acetylcholine regulates insulin secretion / chemosensory behavior / response to fibroblast growth factor / PLC beta mediated events / entrainment of circadian clock / phospholipase C-activating dopamine receptor signaling pathway / cellular response to peptide / regulation of platelet activation ...Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / bile acid secretion / Acetylcholine regulates insulin secretion / chemosensory behavior / response to fibroblast growth factor / PLC beta mediated events / entrainment of circadian clock / phospholipase C-activating dopamine receptor signaling pathway / cellular response to peptide / regulation of platelet activation / cellular response to vitamin D / phototransduction, visible light / phosphatidylinositol phospholipase C activity / Class C/3 (Metabotropic glutamate/pheromone receptors) / calcium ion import / glutamate receptor signaling pathway / regulation of canonical Wnt signaling pathway / positive regulation of positive chemotaxis / fat pad development / amino acid binding / cellular response to hepatocyte growth factor stimulus / branching morphogenesis of an epithelial tube / positive regulation of calcium ion import / action potential / regulation of calcium ion transport / cellular response to low-density lipoprotein particle stimulus / detection of calcium ion / photoreceptor outer segment / anatomical structure morphogenesis / positive regulation of vasoconstriction / axon terminus / JNK cascade / chloride transmembrane transport / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / GTPase activator activity / ossification / G-protein beta/gamma-subunit complex binding / response to ischemia / G protein-coupled receptor binding / G protein-coupled receptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / cellular response to glucose stimulus / negative regulation of protein kinase activity / positive regulation of insulin secretion / Olfactory Signaling Pathway / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G beta:gamma signalling through CDC42 / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / intracellular calcium ion homeostasis / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / vasodilation / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / blood coagulation / 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 (12/13) signalling events / extracellular vesicle / integrin binding / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / cellular response to hypoxia / fibroblast proliferation / G alpha (s) signalling events / basolateral plasma membrane / G alpha (q) signalling events / nuclear membrane / transmembrane transporter binding / Ras protein signal transduction 類似検索 - 分子機能
GPCR, family 3, extracellular calcium-sensing receptor-related / G-protein alpha subunit, group Q / G-protein coupled receptors family 3 signature 1. / G-protein coupled receptors family 3 signature 2. / GPCR, family 3, nine cysteines domain / GPCR, family 3, nine cysteines domain superfamily / Nine Cysteines Domain of family 3 GPCR / GPCR, family 3, conserved site / G-protein coupled receptors family 3 signature 3. / GPCR, family 3 ...GPCR, family 3, extracellular calcium-sensing receptor-related / G-protein alpha subunit, group Q / G-protein coupled receptors family 3 signature 1. / G-protein coupled receptors family 3 signature 2. / GPCR, family 3, nine cysteines domain / GPCR, family 3, nine cysteines domain superfamily / Nine Cysteines Domain of family 3 GPCR / GPCR, family 3, conserved site / G-protein coupled receptors family 3 signature 3. / GPCR, family 3 / G-protein coupled receptors family 3 profile. / GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR / G protein alpha subunit, helical insertion / G protein alpha subunit / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I / 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 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
Extracellular calcium-sensing receptor / Guanine nucleotide-binding protein G(q) subunit alpha / 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 類似検索 - 構成要素
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)
5R01DK132902-02
米国
引用
ジャーナル: Nature / 年: 2024 タイトル: Allosteric modulation and G-protein selectivity of the Ca-sensing receptor. 著者: Feng He / Cheng-Guo Wu / Yang Gao / Sabrina N Rahman / Magda Zaoralová / Makaía M Papasergi-Scott / Ting-Jia Gu / Michael J Robertson / Alpay B Seven / Lingjun Li / Jesper M Mathiesen / Georgios Skiniotis / 要旨: The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor (GPCR) that has a central role in regulating systemic calcium homeostasis. Here we use cryo-electron microscopy and ...The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor (GPCR) that has a central role in regulating systemic calcium homeostasis. Here we use cryo-electron microscopy and functional assays to investigate the activation of human CaSR embedded in lipid nanodiscs and its coupling to functional G versus G proteins in the presence and absence of the calcimimetic drug cinacalcet. High-resolution structures show that both G and G drive additional conformational changes in the activated CaSR dimer to stabilize a more extensive asymmetric interface of the seven-transmembrane domain (7TM) that involves key protein-lipid interactions. Selective G and G coupling by the receptor is achieved through substantial rearrangements of intracellular loop 2 and the C terminus, which contribute differentially towards the binding of the two G-protein subtypes, resulting in distinct CaSR-G-protein interfaces. The structures also reveal that natural polyamines target multiple sites on CaSR to enhance receptor activation by zipping negatively charged regions between two protomers. Furthermore, we find that the amino acid L-tryptophan, a well-known ligand of CaSR extracellular domains, occupies the 7TM bundle of the G-protein-coupled protomer at the same location as cinacalcet and other allosteric modulators. Together, these results provide a framework for G-protein activation and selectivity by CaSR, as well as its allosteric modulation by endogenous and exogenous ligands.