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- PDB-7f16: Cryo-EM structure of parathyroid hormone receptor type 2 in compl... -

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Basic information

Entry
Database: PDB / ID: 7f16
TitleCryo-EM structure of parathyroid hormone receptor type 2 in complex with a tuberoinfundibular peptide of 39 residues and G protein
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Nanobody-35
  • Parathyroid hormone 2 receptor
  • Tuberoinfundibular peptide of 39 residues
KeywordsSIGNALING PROTEIN / Complex / G protein / GPCR / PTH2R
Function / homology
Function and homology information


parathyroid hormone receptor activity / 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 ...parathyroid hormone receptor activity / 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 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 / Class B/2 (Secretin family receptors) / G alpha (i) signalling events / 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 / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / alkylglycerophosphoethanolamine phosphodiesterase activity / 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 / G alpha (s) signalling events / G alpha (q) signalling events / 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 / plasma membrane => GO:0005886 / peptide hormone binding / PKA activation in glucagon signalling / hair follicle placode formation / mu-type opioid receptor binding / photoreceptor outer segment / developmental growth / corticotropin-releasing hormone receptor 1 binding / intracellular transport / D1 dopamine receptor binding / neuropeptide signaling pathway / Hedgehog 'off' state / beta-2 adrenergic receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / negative regulation of inflammatory response to antigenic stimulus / cardiac muscle cell apoptotic process / activation of adenylate cyclase activity / adenylate cyclase activator activity / photoreceptor inner segment / trans-Golgi network membrane / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / G-protein beta/gamma-subunit complex binding / bone development / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / cognition / platelet aggregation / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / 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 / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / GPER1 signaling / G-protein beta-subunit binding / heterotrimeric G-protein complex / sensory perception of smell / signaling receptor complex adaptor activity / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cold-induced thermogenesis / G alpha (i) signalling events / positive regulation of cytosolic calcium ion concentration
Similarity search - Function
Tuberoinfundibular peptide of 39 residues / TIP39 peptide / 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 ...Tuberoinfundibular peptide of 39 residues / TIP39 peptide / 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. / 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
CHOLESTEROL / PALMITIC ACID / Parathyroid hormone 2 receptor / 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 / Tuberoinfundibular peptide of 39 residues
Similarity search - Component
Biological speciesHomo sapiens (human)
Rattus norvegicus (Norway rat)
Bos taurus (cattle)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsWang, X. / Cheng, X. / Zhao, L.H. / Wang, Y. / Ye, C. / Zou, X. / Dai, A. / Cong, Z. / Chen, J. / Zhou, Q. ...Wang, X. / Cheng, X. / Zhao, L.H. / Wang, Y. / Ye, C. / Zou, X. / Dai, A. / Cong, Z. / Chen, J. / Zhou, Q. / Xia, T. / Jiang, H. / Xu, H.E. / Yang, D. / Wang, M.W.
Funding support China, 7items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81872915 China
National Natural Science Foundation of China (NSFC)82073904 China
National Natural Science Foundation of China (NSFC)32071203 China
National Natural Science Foundation of China (NSFC)81773792 China
National Natural Science Foundation of China (NSFC)81973373 China
National Natural Science Foundation of China (NSFC)21704064 China
Ministry of Science and Technology (MoST, China)2018YFA0507002 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2021
Title: Molecular insights into differentiated ligand recognition of the human parathyroid hormone receptor 2.
Authors: Xi Wang / Xi Cheng / Lihua Zhao / Yuzhe Wang / Chenyu Ye / Xinyu Zou / Antao Dai / Zhaotong Cong / Jian Chen / Qingtong Zhou / Tian Xia / Hualiang Jiang / H Eric Xu / Dehua Yang / Ming-Wei Wang /
Abstract: The parathyroid hormone receptor 2 (PTH2R) is a class B1 G protein-coupled receptor (GPCR) involved in the regulation of calcium transport, nociception mediation, and wound healing. Naturally ...The parathyroid hormone receptor 2 (PTH2R) is a class B1 G protein-coupled receptor (GPCR) involved in the regulation of calcium transport, nociception mediation, and wound healing. Naturally occurring mutations in PTH2R were reported to cause hereditary diseases, including syndromic short stature. Here, we report the cryogenic electron microscopy structure of PTH2R bound to its endogenous ligand, tuberoinfundibular peptide (TIP39), and a heterotrimeric G protein at a global resolution of 2.8 Å. The structure reveals that TIP39 adopts a unique loop conformation at the N terminus and deeply inserts into the orthosteric ligand-binding pocket in the transmembrane domain. Molecular dynamics simulation and site-directed mutagenesis studies uncover the basis of ligand specificity relative to three PTH2R agonists, TIP39, PTH, and PTH-related peptide. We also compare the action of TIP39 with an antagonist lacking six residues from the peptide N terminus, TIP(7-39), which underscores the indispensable role of the N terminus of TIP39 in PTH2R activation. Additionally, we unveil that a disease-associated mutation G258D significantly diminished cAMP accumulation induced by TIP39. Together, these results not only provide structural insights into ligand specificity and receptor activation of class B1 GPCRs but also offer a foundation to systematically rationalize the available pharmacological data to develop therapies for various disorders associated with PTH2R.
History
DepositionJun 8, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 18, 2021Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
R: Parathyroid hormone 2 receptor
P: Tuberoinfundibular peptide of 39 residues
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-35
hetero molecules


Theoretical massNumber of molelcules
Total (without water)166,62716
Polymers163,5426
Non-polymers3,08510
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, Nanobody-35
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area22400 Å2
ΔGint-92 kcal/mol
Surface area53850 Å2

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#3: 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
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 40226.992 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gnb1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P54311
#5: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
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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Protein / Protein/peptide / Antibody , 3 types, 3 molecules RPN

#1: Protein Parathyroid hormone 2 receptor / PTH2 receptor


Mass: 49915.051 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTH2R, PTHR2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P49190
#2: Protein/peptide Tuberoinfundibular peptide of 39 residues / TIP39 / Parathyroid hormone 2


Mass: 4512.248 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTH2, TIP39, TIPF39 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q96A98
#6: Antibody Nanobody-35


Mass: 15343.019 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Trichoplusia ni (cabbage looper)

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Non-polymers , 2 types, 10 molecules

#7: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H46O
#8: Chemical
ChemComp-PLM / PALMITIC ACID


Mass: 256.424 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C16H32O2

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Details

Has ligand of interestN

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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: Parathyroid hormone receptor type 2 in complex with a tuberoinfundibular peptide of 39 residues and G protein
Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
SpecimenConc.: 8.5 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
Image recordingElectron dose: 80 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.13_2998: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 301769 / Symmetry type: POINT

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