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Yorodumi- EMDB-34305: the human PTH1 receptor bound to an intracellular biased agonist -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-34305 | |||||||||
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Title | the human PTH1 receptor bound to an intracellular biased agonist | |||||||||
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Sample |
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Keywords | G protein-coupled receptor / membrane protein / SIGNALING PROTEIN | |||||||||
Function / homology | Function and homology information 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 / G protein-coupled peptide receptor activity / 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 / Class B/2 (Secretin family receptors) / 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 / osteoblast development / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / G alpha (q) signalling events / positive regulation of inositol phosphate biosynthetic process / 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 / bone mineralization / peptide hormone binding / PKA activation in glucagon signalling / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / 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 / chondrocyte differentiation / beta-2 adrenergic receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / cell maturation / bone resorption / cardiac muscle cell apoptotic process / activation of adenylate cyclase activity / adenylate cyclase activator activity / photoreceptor inner segment / trans-Golgi network membrane / skeletal system development / insulin-like growth factor receptor binding / ionotropic glutamate receptor binding / G-protein beta/gamma-subunit complex binding / bone development / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / cognition / platelet aggregation / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / intracellular calcium ion homeostasis / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / : / GPER1 signaling / G-protein beta-subunit binding / heterotrimeric G-protein complex / sensory perception of smell Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Rattus norvegicus (Norway rat) / Bos taurus (cattle) / unidentified (others) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||
Authors | Kobayashi K / Kusakizako T / Okamoto HH / Nureki O / Yamashita K / Nishizawa T / Kato HE | |||||||||
Funding support | Japan, 1 items
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Citation | Journal: Nature / Year: 2023 Title: Class B1 GPCR activation by an intracellular agonist. Authors: Kazuhiro Kobayashi / Kouki Kawakami / Tsukasa Kusakizako / Atsuhiro Tomita / Michihiro Nishimura / Kazuhiro Sawada / Hiroyuki H Okamoto / Suzune Hiratsuka / Gaku Nakamura / Riku Kuwabara / ...Authors: 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 / Abstract: 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. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_34305.map.gz | 1.9 MB | EMDB map data format | |
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Header (meta data) | emd-34305-v30.xml emd-34305.xml | 24.2 KB 24.2 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_34305_fsc.xml | 7.5 KB | Display | FSC data file |
Images | emd_34305.png | 117.7 KB | ||
Masks | emd_34305_msk_1.map | 12.4 MB | Mask map | |
Others | emd_34305_half_map_1.map.gz emd_34305_half_map_2.map.gz | 11.4 MB 11.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-34305 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-34305 | HTTPS FTP |
-Validation report
Summary document | emd_34305_validation.pdf.gz | 772.2 KB | Display | EMDB validaton report |
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Full document | emd_34305_full_validation.pdf.gz | 771.8 KB | Display | |
Data in XML | emd_34305_validation.xml.gz | 12.9 KB | Display | |
Data in CIF | emd_34305_validation.cif.gz | 16.6 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-34305 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-34305 | HTTPS FTP |
-Related structure data
Related structure data | 8gw8MC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_34305.map.gz / Format: CCP4 / Size: 12.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.10667 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_34305_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_34305_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_34305_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
+Entire : the human PTH1 receptor bound to an intracellular biased agonist
+Supramolecule #1: the human PTH1 receptor bound to an intracellular biased agonist
+Supramolecule #2: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
+Supramolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Supramolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Supramolecule #5: nanobody Nb35
+Supramolecule #6: Parathyroid hormone/parathyroid hormone-related peptide receptor
+Macromolecule #1: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit...
+Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #4: Nanobody-35
+Macromolecule #5: Parathyroid hormone/parathyroid hormone-related peptide receptor
+Macromolecule #6: PCO-371
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 7 mg/mL |
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Buffer | pH: 9 |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 54.578 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.6 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |