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- PDB-7vvo: PTH-bound human PTH1R in complex with Gs (class5) -

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Entry
Database: PDB / ID: 7vvo
TitlePTH-bound human PTH1R in complex with Gs (class5)
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Parathyroid hormone
  • Parathyroid hormone/parathyroid hormone-related peptide receptor
  • nanobody Nb35
KeywordsSIGNALING PROTEIN / G protein-coupled receptor / membrane protein
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 / 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 / Vasopressin regulates renal water homeostasis via Aquaporins / G protein-coupled peptide receptor activity / 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) / 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 (i) signalling events / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / osteoblast development / alkylglycerophosphoethanolamine phosphodiesterase activity / 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 / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / peptide hormone receptor binding / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / bone mineralization / PKA activation in glucagon signalling / peptide hormone binding / Rho protein signal transduction / hair follicle placode formation / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / developmental growth / positive regulation of glycogen biosynthetic process / photoreceptor outer segment / D1 dopamine receptor binding / intracellular transport / renal water homeostasis / bone resorption / chondrocyte differentiation / Hedgehog 'off' state / positive regulation of bone mineralization / response to cadmium ion / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / cell maturation / homeostasis of number of cells within a tissue / cardiac muscle cell apoptotic process / cellular response to glucagon stimulus / adenylate cyclase activator activity / regulation of insulin secretion / photoreceptor inner segment / 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
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 / 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. / 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
Similarity search - Domain/homology
Parathyroid hormone / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Parathyroid hormone/parathyroid hormone-related peptide receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Rattus norvegicus (Norway rat)
Bos taurus (cattle)
unidentified (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.1 Å
AuthorsKobayashi, K. / Kusakizako, T. / Miyauchi, H. / Tomita, A. / Kobayashi, K. / Shihoya, W. / Yamashita, K. / Nishizawa, T. / Kato, H.E. / Nureki, O.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS) Japan
CitationJournal: Mol Cell / Year: 2022
Title: Endogenous ligand recognition and structural transition of a human PTH receptor.
Authors: Kazuhiro Kobayashi / Kouki Kawakami / Tsukasa Kusakizako / Hirotake Miyauchi / Atsuhiro Tomita / Kan Kobayashi / Wataru Shihoya / Keitaro Yamashita / Tomohiro Nishizawa / Hideaki E Kato / ...Authors: Kazuhiro Kobayashi / Kouki Kawakami / Tsukasa Kusakizako / Hirotake Miyauchi / Atsuhiro Tomita / Kan Kobayashi / Wataru Shihoya / Keitaro Yamashita / Tomohiro Nishizawa / Hideaki E Kato / Asuka Inoue / Osamu Nureki /
Abstract: Endogenous parathyroid hormone (PTH) and PTH-related peptide (PTHrP) bind to the parathyroid hormone receptor 1 (PTH1R) and activate the stimulatory G-protein (Gs) signaling pathway. Intriguingly, ...Endogenous parathyroid hormone (PTH) and PTH-related peptide (PTHrP) bind to the parathyroid hormone receptor 1 (PTH1R) and activate the stimulatory G-protein (Gs) signaling pathway. Intriguingly, the two ligands have distinct signaling and physiological properties: PTH evokes prolonged Gs activation, whereas PTHrP evokes transient Gs activation with reduced bone-resorption effects. The distinct molecular actions are ascribed to the differences in ligand recognition and dissociation kinetics. Here, we report cryoelectron microscopic structures of six forms of the human PTH1R-Gs complex in the presence of PTH or PTHrP at resolutions of 2.8 -4.1 Å. A comparison of the PTH-bound and PTHrP-bound structures reveals distinct ligand-receptor interactions underlying the ligand affinity and selectivity. Furthermore, five distinct PTH-bound structures, combined with computational analyses, provide insights into the unique and complex process of ligand dissociation from the receptor and shed light on the distinct durations of signaling induced by PTH and PTHrP.
History
DepositionNov 6, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 3, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 15, 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 30, 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: nanobody Nb35
P: Parathyroid hormone
R: Parathyroid hormone/parathyroid hormone-related peptide receptor


Theoretical massNumber of molelcules
Total (without water)163,9546
Polymers163,9546
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
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: 44255.664 Da / Num. of mol.: 1 / Mutation: G45E, E46N, L59Y, A245D, S248D, H358A, C361I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P63092
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38744.371 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gnb1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P54311
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7547.685 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63212

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Antibody / Protein/peptide / Protein , 3 types, 3 molecules NPR

#4: Antibody nanobody Nb35


Mass: 15015.728 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) unidentified (others) / Production host: Escherichia coli (E. coli)
#5: Protein/peptide Parathyroid hormone / Teriparatide / PTH / Parathormone / Parathyrin


Mass: 4125.778 Da / Num. of mol.: 1 / 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: 54264.359 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTH1R, PTHR, PTHR1 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q03431

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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

Component
IDNameTypeEntity IDParent-IDSource
1endogenous ligand-bound the human PTH receptor in complex with GsCOMPLEXall0MULTIPLE SOURCES
2Guanine nucleotide-binding protein G(s) subunit alpha isoforms shortCOMPLEX#11RECOMBINANT
3Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1COMPLEX#21RECOMBINANT
4Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2COMPLEX#31RECOMBINANT
5nanobody Nb35COMPLEX#41RECOMBINANT
6PTHrPCOMPLEX#51SYNTHETIC
7Parathyroid hormone/parathyroid hormone-related peptide receptorCOMPLEX#61RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
22Rattus norvegicus (Norway rat)10116
33Bos taurus (cattle)9913
44unidentified (others)32644
56Homo sapiens (human)9096
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
11Escherichia coli (E. coli)562
22Spodoptera frugiperda (fall armyworm)7108
33Spodoptera frugiperda (fall armyworm)7108
44Escherichia coli (E. coli)562
56Homo sapiens (human)9606
Buffer solutionpH: 7.4
SpecimenConc.: 10 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 64.319 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0298 / Classification: refinement
CTF correctionType: NONE
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 29736 / Symmetry type: POINT
RefinementResolution: 4.1→137.23 Å / Cor.coef. Fo:Fc: 0.935 / SU B: 36.64 / SU ML: 0.498 / ESU R: 0.724
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.346 --
obs0.346 62283 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 113.302 Å2
Refinement stepCycle: 1 / Total: 7944
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0090.0138094
ELECTRON MICROSCOPYr_bond_other_d0.0140.0157398
ELECTRON MICROSCOPYr_angle_refined_deg1.5121.63810999
ELECTRON MICROSCOPYr_angle_other_deg1.3361.58116847
ELECTRON MICROSCOPYr_dihedral_angle_1_deg6.69351046
ELECTRON MICROSCOPYr_dihedral_angle_2_deg32.28921.612397
ELECTRON MICROSCOPYr_dihedral_angle_3_deg17.576151226
ELECTRON MICROSCOPYr_dihedral_angle_4_deg15.9091554
ELECTRON MICROSCOPYr_chiral_restr0.0760.21117
ELECTRON MICROSCOPYr_gen_planes_refined0.0070.029385
ELECTRON MICROSCOPYr_gen_planes_other0.0030.021963
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it18.42112.1564223
ELECTRON MICROSCOPYr_mcbond_other18.42312.1554222
ELECTRON MICROSCOPYr_mcangle_it29.1818.1725256
ELECTRON MICROSCOPYr_mcangle_other29.17818.1755257
ELECTRON MICROSCOPYr_scbond_it18.15712.9873871
ELECTRON MICROSCOPYr_scbond_other18.15512.9893872
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other29.71818.975743
ELECTRON MICROSCOPYr_long_range_B_refined47.8433.991125797
ELECTRON MICROSCOPYr_long_range_B_other47.8433.99125797
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 4.1→4.207 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.743 4579 -
obs--100 %

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