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Open data
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Basic information
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Title | Human PTH1R in complex with Abaloparatide and Gs | |||||||||||||||
![]() | Consensus map sharpened; rescaled to 0.85 angstrom/px | |||||||||||||||
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![]() | GPCR / agonist / hormone / MEMBRANE PROTEIN | |||||||||||||||
Function / homology | ![]() parathyroid hormone receptor activity / G protein-coupled peptide receptor activity / Class B/2 (Secretin family receptors) / osteoblast development / 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 ...parathyroid hormone receptor activity / G protein-coupled peptide receptor activity / Class B/2 (Secretin family receptors) / osteoblast development / 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 / developmental growth / D1 dopamine receptor binding / intracellular transport / chondrocyte differentiation / Hedgehog 'off' state / bone resorption / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / cell maturation / adenylate cyclase activator activity / trans-Golgi network membrane / skeletal system development / G-protein beta/gamma-subunit complex binding / bone development / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / cognition / platelet aggregation / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / intracellular calcium ion homeostasis / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / sensory perception of smell / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / positive regulation of cold-induced thermogenesis / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / basolateral plasma membrane / in utero embryonic development / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / receptor complex / G protein-coupled receptor signaling pathway / apical plasma membrane / negative regulation of cell population proliferation / lysosomal membrane / GTPase activity / synapse / positive regulation of cell population proliferation / protein-containing complex binding / GTP binding / signal transduction / protein homodimerization activity / extracellular exosome / membrane / nucleus / metal ion binding / plasma membrane Similarity search - Function | |||||||||||||||
Biological species | ![]() ![]() ![]() | |||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.09 Å | |||||||||||||||
![]() | Cary BP / Belousoff MJ / Piper SJ / Wootten D / Sexton PM | |||||||||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 85.3 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 31.7 KB 31.7 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 9.5 KB | Display | ![]() |
Images | ![]() | 53.5 KB | ||
Masks | ![]() | 91.1 MB | ![]() | |
Others | ![]() ![]() ![]() ![]() ![]() | 45.7 MB 44.2 MB 45.7 MB 84.6 MB 84.7 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8flsMC ![]() 8flqC ![]() 8flrC ![]() 8fltC ![]() 8fluC C: citing same article ( M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Consensus map sharpened; rescaled to 0.85 angstrom/px | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.85 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
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Density Histograms |
-Additional map: Consensus map unsharpened; rescaled to 0.85 angstrom/px
File | emd_29285_additional_1.map | ||||||||||||
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Annotation | Consensus map unsharpened; rescaled to 0.85 angstrom/px | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: Local refinement on receptor; rescaled to 0.85 angstrom/px
File | emd_29285_additional_2.map | ||||||||||||
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Annotation | Local refinement on receptor; rescaled to 0.85 angstrom/px | ||||||||||||
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Density Histograms |
-Additional map: unsharpened consensus map; original pixel size
File | emd_29285_additional_3.map | ||||||||||||
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Annotation | unsharpened consensus map; original pixel size | ||||||||||||
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Density Histograms |
-Half map: Half-map
File | emd_29285_half_map_1.map | ||||||||||||
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Annotation | Half-map | ||||||||||||
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Density Histograms |
-Half map: Half-map
File | emd_29285_half_map_2.map | ||||||||||||
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Annotation | Half-map | ||||||||||||
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Density Histograms |
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Sample components
-Entire : Abaloparatide bound to the PTH1R in complex with G protein
Entire | Name: Abaloparatide bound to the PTH1R in complex with G protein |
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Components |
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-Supramolecule #1: Abaloparatide bound to the PTH1R in complex with G protein
Supramolecule | Name: Abaloparatide bound to the PTH1R in complex with G protein type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Macromolecule | Name: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 45.683434 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE ...String: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE YQLIDCAQYF LDKIDVIKQA DYVPSDQDLL RCRVLTSGIF ETKFQVDKVN FHMFDVGAQR DERRKWIQCF ND VTAIIFV VASSSYNMVI REDNQTNRLQ AALKLFDSIW NNKWLRDTSV ILFLNKQDLL AEKVLAGKSK IEDYFPEFAR YTT PEDATP EPGEDPRVTR AKYFIRDEFL RISTASGDGR HYCYPHFTCA VDTENIRRVF NDCRDIIQRM HLRQYELL |
-Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 37.413863 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: QSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...String: QSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD INAICFFPNG NA FATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGV TDDGMA VATGSWDSFL KIWN |
-Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 6.375332 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: NTASIAQARK LVEQLKMEAN IDRIKVSKAA ADLMAYCEAH AKEDPLLTPV PASENPFR |
-Macromolecule #4: Nanobody35
Macromolecule | Name: Nanobody35 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 13.885439 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPE DTAVYYCARC PAPFTRDCFD VTSTTYAYRG QGTQVTVSS |
-Macromolecule #5: Abaloparatide
Macromolecule | Name: Abaloparatide / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: synthetic construct (others) |
Molecular weight | Theoretical: 3.971654 KDa |
Sequence | String: AVSEHQLLHD KGKSIQDLRR RELLEKLL(AIB)K LHTA |
-Macromolecule #6: Parathyroid hormone/parathyroid hormone-related peptide receptor
Macromolecule | Name: Parathyroid hormone/parathyroid hormone-related peptide receptor type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 69.513758 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MKTIIALSYI FCLVFADYKD DDDLEVLFQG PADDVMTKEE QIFLLHRAQA QCEKRLKEVL QRPASIMESD KGWTSASTSG KPRKDKASG KLYPESEEDK EAPTGSRYRG RPCLPEWDHI LCWPLGAPGE VVAVPCPDYI YDFNHKGHAY RRCDRNGSWE L VPGHNRTW ...String: MKTIIALSYI FCLVFADYKD DDDLEVLFQG PADDVMTKEE QIFLLHRAQA QCEKRLKEVL QRPASIMESD KGWTSASTSG KPRKDKASG KLYPESEEDK EAPTGSRYRG RPCLPEWDHI LCWPLGAPGE VVAVPCPDYI YDFNHKGHAY RRCDRNGSWE L VPGHNRTW ANYSECVKFL TNETREREVF DRLGMIYTVG YSVSLASLTV AVLILAYFRR LHCTRNYIHM HLFLSFMLRA VS IFVKDAV LYSGATLDEA ERLTEEELRA IAQAPPPPAT AAAGYAGCRV AVTFFLYFLA TNYYWILVEG LYLHSLIFMA FFS EKKYLW GFTVFGWGLP AVFVAVWVSV RATLANTGCW DLSSGNKKWI IQVPILASIV LNFILFINIV RVLATKLRET NAGR CDTRQ QYRKLLKSTL VLMPLFGVHY IVFMATPYTE VSGTLWQVQM HYEMLFNSFQ GFFVAIIYCF CNGEVQAEIK KSWSR WTLA LDFKRKARSG SSSYSYGPMV SHTSVTNVGP RVGLGLPLSP RLLPTATTNG HPQLPGHAKP GTPALETLET TPPAMA APK DDGFLNGSCS GLDEEASGPE RPPALLQEEW ETVMPAGLEV LFQGPHHHHH HHH |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 3.9 mg/mL | |||||||||||||||||||||
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Buffer | pH: 7.4 Component:
Details: Buffer also contained 2 micromolar abaloparatide peptide. | |||||||||||||||||||||
Grid | Model: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR / Details: 20 mA current, negative polarity | |||||||||||||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | TFS GLACIOS |
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Image recording | Film or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 2317 / Average exposure time: 8.29 sec. / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.3 µm / Nominal defocus min: 0.6 µm |
Sample stage | Cooling holder cryogen: NITROGEN |