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- PDB-7vvk: PTH-bound human PTH1R in complex with Gs (class1) -

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Basic information

Entry
Database: PDB / ID: 7vvk
TitlePTH-bound human PTH1R in complex with Gs (class1)
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Parathyroid hormone/parathyroid hormone-related peptide receptor
  • Parathyroid hormone
  • nanobody Nb35
KeywordsSIGNALING PROTEIN / G protein-coupled receptor / membrane protein
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 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 / Ca2+ pathway / Activation of G protein gated Potassium channels / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G protein-coupled peptide receptor activity / 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 / G alpha (i) signalling events / negative regulation of chondrocyte differentiation / Thrombin signalling through proteinase activated receptors (PARs) / 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 / alkylglycerophosphoethanolamine phosphodiesterase activity / 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 / G alpha (z) signalling events / Extra-nuclear estrogen signaling / osteoblast development / G alpha (s) signalling events / G alpha (q) signalling events / positive regulation of inositol phosphate biosynthetic process / peptide hormone receptor binding / 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 / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / PKA activation in glucagon signalling / peptide hormone binding / Rho protein signal transduction / activation of phospholipase C activity / hair follicle placode formation / intracellular transport / photoreceptor outer segment / D1 dopamine receptor binding / developmental growth / positive regulation of glycogen biosynthetic process / chondrocyte differentiation / Hedgehog 'off' state / positive regulation of bone mineralization / response to cadmium ion / positive regulation of cAMP-mediated signaling / adenylate cyclase-activating adrenergic receptor signaling pathway / homeostasis of number of cells within a tissue / cell maturation / bone resorption / cardiac muscle cell apoptotic process / activation of adenylate cyclase activity / photoreceptor inner segment / adenylate cyclase activator activity / trans-Golgi network membrane / skeletal system development / positive regulation of glucose import / 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. / 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 alpha subunit, group S / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / 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 / 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 / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / 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: 3.3 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

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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
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: 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: G45D, E46N, L59Y, A245D, S248D, H358A, C361I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Escherichia coli (E. coli) / 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 / / 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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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
6Parathyroid hormoneCOMPLEX#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)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
11Escherichia coli (E. coli)562
22Spodoptera frugiperda (fall armyworm)7108
33Spodoptera frugiperda (fall armyworm)7108
44Escherichia coli (E. coli)562
56Homo sapiens (human)9606HEK293
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 FIELDBright-field microscopy / 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: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 65498 / Symmetry type: POINT
RefinementResolution: 3.3→135.01 Å / Cor.coef. Fo:Fc: 0.885 / SU B: 20.795 / SU ML: 0.327 / ESU R: 0.393
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.35308 --
obs0.35308 109093 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 102.901 Å2
Refinement stepCycle: 1 / Total: 8518
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0110.0138693
ELECTRON MICROSCOPYr_bond_other_d0.0250.0157938
ELECTRON MICROSCOPYr_angle_refined_deg1.5181.63611809
ELECTRON MICROSCOPYr_angle_other_deg1.5731.5818074
ELECTRON MICROSCOPYr_dihedral_angle_1_deg5.98651108
ELECTRON MICROSCOPYr_dihedral_angle_2_deg31.21321.458432
ELECTRON MICROSCOPYr_dihedral_angle_3_deg15.192151332
ELECTRON MICROSCOPYr_dihedral_angle_4_deg14.2721558
ELECTRON MICROSCOPYr_chiral_restr0.080.21180
ELECTRON MICROSCOPYr_gen_planes_refined0.0080.0210042
ELECTRON MICROSCOPYr_gen_planes_other0.0050.022146
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_it12.35911.1144471
ELECTRON MICROSCOPYr_mcbond_other12.3611.1124470
ELECTRON MICROSCOPYr_mcangle_it18.86616.6485566
ELECTRON MICROSCOPYr_mcangle_other18.86416.6515567
ELECTRON MICROSCOPYr_scbond_it12.21411.6474222
ELECTRON MICROSCOPYr_scbond_other12.21411.6474222
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other19.71317.0946243
ELECTRON MICROSCOPYr_long_range_B_refined28.843204.76834477
ELECTRON MICROSCOPYr_long_range_B_other28.843204.76434477
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.3→3.386 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.981 7967 -
obs--100 %

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