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Yorodumi- PDB-8ha0: Molecular recognition of two endogenous hormones by the human par... -
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-Basic information
Entry | Database: PDB / ID: 8ha0 | ||||||
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Title | Molecular recognition of two endogenous hormones by the human parathyroid hormone receptor-1 | ||||||
Components |
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Keywords | LIPID BINDING PROTEIN/HORMONE/IMMUNE SYSTEM / PTH1R / GPCR / LIPID BINDING PROTEIN-HORMONE-IMMUNE SYSTEM complex | ||||||
Function / homology | Function and homology information parathyroid hormone receptor binding / type 1 parathyroid hormone receptor binding / negative regulation of bone mineralization involved in bone maturation / negative regulation of apoptotic process in bone marrow cell / positive regulation of osteoclast proliferation / response to parathyroid hormone / macromolecule biosynthetic process / parathyroid hormone receptor activity / hormone-mediated apoptotic signaling pathway / positive regulation of cell proliferation in bone marrow ...parathyroid hormone receptor binding / type 1 parathyroid hormone receptor binding / negative regulation of bone mineralization involved in bone maturation / negative regulation of apoptotic process in bone marrow cell / positive regulation of osteoclast proliferation / response to parathyroid hormone / macromolecule biosynthetic process / parathyroid hormone receptor activity / hormone-mediated apoptotic signaling pathway / positive regulation of cell proliferation in bone marrow / positive regulation of signal transduction / magnesium ion homeostasis / response to fibroblast growth factor / phosphate ion homeostasis / cAMP metabolic process / response to vitamin D / 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 / Ca2+ pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / G protein-coupled peptide receptor activity / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / 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 / negative regulation of chondrocyte differentiation / Class B/2 (Secretin family receptors) / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (i) signalling events / 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 / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / alkylglycerophosphoethanolamine phosphodiesterase activity / osteoblast development / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / Extra-nuclear estrogen signaling / G alpha (z) signalling events / G alpha (s) signalling events / G alpha (q) signalling events / positive regulation of inositol phosphate biosynthetic process / photoreceptor outer segment membrane / peptide hormone receptor binding / 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 / Rho protein signal transduction / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of glycogen biosynthetic process / photoreceptor outer segment / chondrocyte differentiation / bone resorption / response to cadmium ion / positive regulation of bone mineralization / cell maturation / homeostasis of number of cells within a tissue / cardiac muscle cell apoptotic process / photoreceptor inner segment / skeletal system development / positive regulation of D-glucose import / adenylate cyclase-activating G protein-coupled receptor signaling pathway / response to lead ion / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / hormone activity / intracellular calcium ion homeostasis / cellular response to catecholamine stimulus / sensory perception of taste / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / cell-cell signaling / GTPase binding / retina development in camera-type eye Similarity search - Function | ||||||
Biological species | Bos taurus (cattle) Rattus norvegicus (Norway rat) synthetic construct (others) Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.62 Å | ||||||
Authors | Zhao, L. / Xu, H.E. / Yuan, Q. | ||||||
Funding support | China, 1items
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Citation | Journal: Acta Pharmacol Sin / Year: 2023 Title: Molecular recognition of two endogenous hormones by the human parathyroid hormone receptor-1. Authors: Li-Hua Zhao / Qing-Ning Yuan / An-Tao Dai / Xin-Heng He / Chuan-Wei Chen / Chao Zhang / You-Wei Xu / Yan Zhou / Ming-Wei Wang / De-Hua Yang / H Eric Xu / Abstract: Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) are two endogenous hormones recognized by PTH receptor-1 (PTH1R), a member of class B G protein- coupled receptors (GPCRs). Both PTH and ...Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) are two endogenous hormones recognized by PTH receptor-1 (PTH1R), a member of class B G protein- coupled receptors (GPCRs). Both PTH and PTHrP analogs including teriparatide and abaloparatide are approved drugs for osteoporosis, but they exhibit distinct pharmacology. Here we report two cryo-EM structures of human PTH1R bound to PTH and PTHrP in the G protein-bound state at resolutions of 2.62 Å and 3.25 Å, respectively. Detailed analysis of these structures uncovers both common and unique features for the agonism of PTH and PTHrP. Molecular dynamics (MD) simulation together with site-directed mutagenesis studies reveal the molecular basis of endogenous hormones recognition specificity and selectivity to PTH1R. These results provide a rational template for the clinical use of PTH and PTHrP analogs as an anabolic therapy for osteoporosis and other disorders. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8ha0.cif.gz | 250.7 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8ha0.ent.gz | 192.8 KB | Display | PDB format |
PDBx/mmJSON format | 8ha0.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8ha0_validation.pdf.gz | 1.4 MB | Display | wwPDB validaton report |
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Full document | 8ha0_full_validation.pdf.gz | 1.4 MB | Display | |
Data in XML | 8ha0_validation.xml.gz | 44.8 KB | Display | |
Data in CIF | 8ha0_validation.cif.gz | 64.4 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ha/8ha0 ftp://data.pdbj.org/pub/pdb/validation_reports/ha/8ha0 | HTTPS FTP |
-Related structure data
Related structure data | 34585MC 8hafC 8haoC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG
#1: Protein | Mass: 41879.465 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Bos taurus (cattle) / Production host: Trichoplusia ni (cabbage looper) |
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#2: Protein | Mass: 43706.750 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gnb1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P54311 |
#3: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Bos taurus (cattle) / Gene: GNG2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P63212 |
-Antibody / Protein/peptide / Protein , 3 types, 3 molecules NPR
#4: Antibody | Mass: 15343.019 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli) |
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#5: Protein/peptide | Mass: 4125.778 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PTH / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P01270 |
#6: Protein | Mass: 54506.734 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PTH1R, PTHR, PTHR1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q03431 |
-Non-polymers , 2 types, 7 molecules
#7: Chemical | ChemComp-CLR / #8: Chemical | |
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-Details
Has ligand of interest | N |
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Has protein modification | Y |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: PTH-PTHR G protein complex / Type: COMPLEX / Entity ID: #1-#6 / Source: MULTIPLE SOURCES |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Trichoplusia ni (cabbage looper) |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid type: Quantifoil R1.2/1.3 |
Vitrification | Cryogen name: ETHANE / Humidity: 100 % |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 105000 X / Calibrated magnification: 105000 X / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm / Calibrated defocus min: 600 nm / Calibrated defocus max: 2200 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 100 K / Temperature (min): 89 K |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 2.62 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 407467 / Symmetry type: POINT |