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- PDB-8hao: Human parathyroid hormone receptor-1 dimer -

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Basic information

Entry
Database: PDB / ID: 8hao
TitleHuman parathyroid hormone receptor-1 dimer
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Nanobody 35
  • Parathyroid hormone
  • Parathyroid hormone/parathyroid hormone-related peptide receptor
KeywordsLIPID BINDING PROTEIN/HORMONE/IMMUNE SYSTEM / PTH1R / GPCR / LIPID BINDING PROTEIN-HORMONE-IMMUNE SYSTEM complex
Function / homology
Function and homology information


type 1 parathyroid hormone receptor binding / parathyroid hormone receptor binding / negative regulation of bone mineralization involved in bone maturation / positive regulation of osteoclast proliferation / negative regulation of apoptotic process in bone marrow cell / hormone-mediated apoptotic signaling pathway / response to parathyroid hormone / parathyroid hormone receptor activity / positive regulation of cell proliferation in bone marrow / magnesium ion homeostasis ...type 1 parathyroid hormone receptor binding / parathyroid hormone receptor binding / negative regulation of bone mineralization involved in bone maturation / positive regulation of osteoclast proliferation / negative regulation of apoptotic process in bone marrow cell / hormone-mediated apoptotic signaling pathway / response to parathyroid hormone / parathyroid hormone receptor activity / positive regulation of cell proliferation in bone marrow / magnesium ion homeostasis / positive regulation of signal transduction / macromolecule biosynthetic process / response to fibroblast growth factor / phosphate ion homeostasis / cAMP metabolic process / response to vitamin D / G protein-coupled peptide receptor activity / negative regulation of chondrocyte differentiation / Class B/2 (Secretin family receptors) / 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 / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / osteoblast development / 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 / peptide hormone receptor binding / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / bone mineralization / peptide hormone binding / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / Rho protein signal transduction / : / positive regulation of glycogen biosynthetic process / chondrocyte differentiation / positive regulation of bone mineralization / response to cadmium ion / cell maturation / homeostasis of number of cells within a tissue / bone resorption / skeletal system development / positive regulation of glucose import / response to lead ion / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / hormone activity / cellular response to catecholamine stimulus / intracellular calcium ion homeostasis / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / : / cell-cell signaling / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (s) signalling events / regulation of gene expression / basolateral plasma membrane / response to ethanol / in utero embryonic development / cell population proliferation / transcription by RNA polymerase II / receptor ligand activity / cell surface receptor signaling pathway / receptor complex / response to xenobiotic stimulus / apical plasma membrane / G protein-coupled receptor signaling pathway / negative regulation of cell population proliferation / negative regulation of gene expression / GTPase activity / positive regulation of cell population proliferation / positive regulation of gene expression / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular region / membrane / nucleus / plasma membrane / cytoplasm
Similarity search - Function
Parathyroid hormone / Parathyroid hormone/parathyroid hormone-related protein / Parathyroid hormone family / Parathyroid hormone family signature. / Parathyroid hormone / GPCR, family 2, parathyroid hormone receptor / G-protein coupled receptors family 2 signature 1. / Hormone receptor domain / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. ...Parathyroid hormone / Parathyroid hormone/parathyroid hormone-related protein / Parathyroid hormone family / Parathyroid hormone family signature. / Parathyroid hormone / GPCR, family 2, parathyroid hormone receptor / G-protein coupled receptors family 2 signature 1. / Hormone receptor domain / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / 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, 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
Similarity search - Domain/homology
Parathyroid hormone / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Parathyroid hormone/parathyroid hormone-related peptide receptor
Similarity search - Component
Biological speciesBos taurus (cattle)
Rattus norvegicus (Norway rat)
synthetic construct (others)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.76 Å
AuthorsZhao, L. / Xu, H.E. / Yuan, Q.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32071203 China
CitationJournal: 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
DepositionOct 26, 2022Deposition site: PDBJ / Processing site: RCSB
Revision 1.0Dec 21, 2022Provider: repository / Type: Initial release
Revision 1.1May 31, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(s) subunit alpha
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(s) subunit alpha
D: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
E: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
F: Nanobody 35
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
H: Parathyroid hormone
I: Parathyroid hormone/parathyroid hormone-related peptide receptor
N: Nanobody 35
P: Parathyroid hormone
R: Parathyroid hormone/parathyroid hormone-related peptide receptor


Theoretical massNumber of molelcules
Total (without water)334,84212
Polymers334,84212
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Guanine nucleotide-binding protein ... , 3 types, 6 molecules ACBDEG

#1: Protein Guanine nucleotide-binding protein G(s) subunit alpha


Mass: 41879.465 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Production host: Trichoplusia ni (cabbage looper)
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1


Mass: 43706.750 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Production host: Trichoplusia ni (cabbage looper)
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 2
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

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Antibody / Protein/peptide / Protein , 3 types, 6 molecules FNHPIR

#4: Antibody Nanobody 35


Mass: 15343.019 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)
#5: Protein/peptide Parathyroid hormone / PTH / Parathormone / Parathyrin


Mass: 4123.786 Da / Num. of mol.: 2
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 Parathyroid hormone/parathyroid hormone-related peptide receptor / PTH/PTHrP type I receptor / PTH/PTHr receptor / Parathyroid hormone 1 receptor / PTH1 receptor


Mass: 54506.734 Da / Num. of mol.: 2
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

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: PTH-PTHR G protein complex / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: 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 holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 100 K / Temperature (min): 89 K
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.76 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 55858 / Symmetry type: POINT

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