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- PDB-8flq: Human PTH1R in complex with PTH(1-34) and Gs -

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Basic information

Entry
Database: PDB / ID: 8flq
TitleHuman PTH1R in complex with PTH(1-34) and Gs
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Nanobody35
  • Parathyroid hormone
  • Parathyroid hormone/parathyroid hormone-related peptide receptor
KeywordsMEMBRANE PROTEIN / GPCR / agonist / hormone
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 / positive regulation of osteoclast proliferation / negative regulation of apoptotic process in bone marrow cell / response to parathyroid hormone / positive regulation of cell proliferation in bone marrow / macromolecule biosynthetic process / parathyroid hormone receptor activity / hormone-mediated apoptotic signaling pathway ...parathyroid hormone receptor binding / type 1 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 / response to parathyroid hormone / positive regulation of cell proliferation in bone marrow / macromolecule biosynthetic process / parathyroid hormone receptor activity / hormone-mediated apoptotic signaling pathway / magnesium ion homeostasis / positive regulation of signal transduction / response to fibroblast growth factor / phosphate ion homeostasis / cAMP metabolic process / response to vitamin D / Class B/2 (Secretin family receptors) / G protein-coupled peptide receptor activity / negative regulation of chondrocyte differentiation / osteoblast development / peptide hormone receptor binding / positive regulation of inositol phosphate biosynthetic process / 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 / Rho protein signal transduction / developmental growth / chondrocyte differentiation / D1 dopamine receptor binding / positive regulation of glycogen biosynthetic process / bone resorption / positive regulation of bone mineralization / intracellular transport / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / response to cadmium ion / Hedgehog 'off' state / cell maturation / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / homeostasis of number of cells within a tissue / regulation of insulin secretion / cellular response to glucagon stimulus / adenylate cyclase activator activity / trans-Golgi network membrane / skeletal system development / positive regulation of D-glucose import / negative regulation of inflammatory response to antigenic stimulus / response to lead ion / hormone activity / bone development / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / platelet aggregation / Olfactory Signaling Pathway / cognition / 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 / intracellular calcium ion homeostasis / 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 / 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 / adenylate cyclase-activating dopamine receptor signaling pathway / sensory perception of smell / 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 / cell-cell signaling / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / positive regulation of cold-induced thermogenesis
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. / : / 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. / : / 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 / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Parathyroid hormone / 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 / Parathyroid hormone/parathyroid hormone-related peptide receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.55 Å
AuthorsCary, B.P. / Belousoff, M.J. / Piper, S.J. / Wootten, D. / Sexton, P.M.
Funding support Australia, 4items
OrganizationGrant numberCountry
Australian Research Council (ARC)IC200100052 Australia
National Health and Medical Research Council (NHMRC, Australia)1155302 Australia
National Health and Medical Research Council (NHMRC, Australia)1154434 Australia
National Health and Medical Research Council (NHMRC, Australia)1150083 Australia
CitationJournal: Structure / Year: 2023
Title: Molecular insights into peptide agonist engagement with the PTH receptor.
Authors: Brian P Cary / Elliot J Gerrard / Matthew J Belousoff / Madeleine M Fletcher / Yan Jiang / Isabella C Russell / Sarah J Piper / Denise Wootten / Patrick M Sexton /
Abstract: The parathyroid hormone (PTH) 1 receptor (PTH1R) is a G protein-coupled receptor (GPCR) that regulates skeletal development and calcium homeostasis. Here, we describe cryo-EM structures of the PTH1R ...The parathyroid hormone (PTH) 1 receptor (PTH1R) is a G protein-coupled receptor (GPCR) that regulates skeletal development and calcium homeostasis. Here, we describe cryo-EM structures of the PTH1R in complex with fragments of the two hormones, PTH and PTH-related protein, the drug abaloparatide, as well as the engineered tool compounds, long-acting PTH (LA-PTH) and the truncated peptide, M-PTH(1-14). We found that the critical N terminus of each agonist engages the transmembrane bundle in a topologically similar fashion, reflecting similarities in measures of Gαs activation. The full-length peptides induce subtly different extracellular domain (ECD) orientations relative to the transmembrane domain. In the structure bound to M-PTH, the ECD is unresolved, demonstrating that the ECD is highly dynamic when unconstrained by a peptide. High resolutions enabled identification of water molecules near peptide and G protein binding sites. Our results illuminate the action of orthosteric agonists of the PTH1R.
History
DepositionDec 22, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 26, 2023Provider: repository / Type: Initial release
Revision 1.1May 17, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Jun 14, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Nov 13, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update

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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 isoforms short
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: Nanobody35
P: Parathyroid hormone
R: Parathyroid hormone/parathyroid hormone-related peptide receptor


Theoretical massNumber of molelcules
Total (without water)176,9986
Polymers176,9986
Non-polymers00
Water25214
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, 3 molecules ABG

#1: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-stimulating G alpha protein


Mass: 45683.434 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P63092
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37413.863 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 6375.332 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P59768

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Antibody / Protein/peptide / Protein / Non-polymers , 4 types, 17 molecules NPR

#4: Antibody Nanobody35


Mass: 13885.439 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#5: Protein/peptide Parathyroid hormone / PTH / Parathormone / Parathyrin


Mass: 4125.778 Da / Num. of mol.: 1 / Fragment: UNP residues 32-65 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / 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: 69513.758 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
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY

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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 bound to the PTH1R in complex with G protein / Type: COMPLEX / Entity ID: #1-#6 / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4 / Details: Buffer also contained 2 micromolar PTH peptide.
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPESC8H18N2O4S1
2100 mMSodium ChlorideNaCl1
32 mMMagnesium ChlorideMgCl21
40.1 mMTCEPC9H15O6P1
50.01 percentLMNGC47H88O221
60.00006 percentCHSC31H50O41
SpecimenConc.: 3.32 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: 20 mA current, negative polarity / Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 defocus max: 1500 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 3.25 sec. / Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4750

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM software
IDNameVersionCategory
4Gctf1.18CTF correction
10cryoSPARC3.2.0initial Euler assignment
13cryoSPARC3.2.03D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4061235
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.55 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 154694 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0029191
ELECTRON MICROSCOPYf_angle_d0.48212465
ELECTRON MICROSCOPYf_dihedral_angle_d4.341248
ELECTRON MICROSCOPYf_chiral_restr0.041388
ELECTRON MICROSCOPYf_plane_restr0.0041590

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