Target Information

Target General Information

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Target ID

T22032 (Former ID: TTDC00041)

Target Name

Parathyroid hormone receptor (PTH2R)

Synonyms

PTHR2; PTH2R; PTH2 receptor

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Gene Name

PTH2R

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Low bone mass disorder [ICD-11: FB83]

Function

This is a specific receptor for parathyroid hormone. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. PTH2R may be responsible for PTH effects in a number of physiological systems. It may play asignificant role in pancreatic function. PTH2R presence in neurons indicates that it may function as a neurotransmitter receptor.

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BioChemical Class

GPCR secretin

UniProt ID

PTH2R_HUMAN

Sequence

MAGLGASLHVWGWLMLGSCLLARAQLDSDGTITIEEQIVLVLKAKVQCELNITAQLQEGE
GNCFPEWDGLICWPRGTVGKISAVPCPPYIYDFNHKGVAFRHCNPNGTWDFMHSLNKTWA
NYSDCLRFLQPDISIGKQEFFERLYVMYTVGYSISFGSLAVAILIIGYFRRLHCTRNYIH
MHLFVSFMLRATSIFVKDRVVHAHIGVKELESLIMQDDPQNSIEATSVDKSQYIGCKIAV
VMFIYFLATNYYWILVEGLYLHNLIFVAFFSDTKYLWGFILIGWGFPAAFVAAWAVARAT
LADARCWELSAGDIKWIYQAPILAAIGLNFILFLNTVRVLATKIWETNAVGHDTRKQYRK
LAKSTLVLVLVFGVHYIVFVCLPHSFTGLGWEIRMHCELFFNSFQGFFVSIIYCYCNGEV
QAEVKKMWSRWNLSVDWKRTPPCGSRRCGSVLTTVTHSTSSQSQVAASTRMVLISGKAAK
IASRQPDSHITLPGYVWSNSEQDCLPHSFHEETKEDSGRQGDDILMEKPSRPMESNPDTE
GCQGETEDVL

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 5 Clinical Trial Drugs

BA-058

Drug Info

Phase 3

Osteoporosis

[2], [3]

GSK768974

Drug Info

Phase 2

Osteoporosis

[4]

NPSP-795

Drug Info

Phase 2

Osteoporosis

[5]

UNI-PH (1-34)

Drug Info

Phase 2

Osteoporosis

[6]

PTH(7-34) liposomal cream

Drug Info

Phase 1

Alopecia

[7]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

Semparatide

Drug Info

Discontinued in Phase 2

Osteoporosis

[8]

Mode of Action

[+] 2 Modes of Action

Modulator

[+] 10 Modulator drugs

BA-058

Drug Info

[1]

NPSP-795

Drug Info

[10]

UNI-PH (1-34)

Drug Info

[11]

PTH(7-34) liposomal cream

Drug Info

[12]

Semparatide

Drug Info

[13]

BB-PTH 1-84

Drug Info

[10]

Hemoparatide

Drug Info

[14]

PTHr pepducins

Drug Info

[10]

SDZ-PTS-893

Drug Info

[15]

ZP-2307

Drug Info

[10]

Agonist

[+] 1 Agonist drugs

GSK768974

Drug Info

[9]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: Cholesterol

Ligand Info

Structure Description

Cryo-EM structure of parathyroid hormone receptor type 2 in complex with a tuberoinfundibular peptide of 39 residues and G protein

PDB:7F16

Method

Electron microscopy

Resolution

2.80 Å

Mutation

Yes

[16]

PDB Sequence

TITIEEQIVL

⁴⁰

VLKAKVQCEL

⁵⁰

NITAQLQEGE

⁶⁰

GNCFPEWDGL

⁷⁰

ICWPRGTVGK

⁸⁰

ISAVPCPPYI

⁹⁰

YDFNHKGVAF

¹⁰⁰

RHCNPNGTWD

¹¹⁰

FMHSLNKTWA

¹²⁰

NYSDCLRFLQ

¹³⁰

PDISIGKQEF

¹⁴⁰

FERLYVMYTV

¹⁵⁰

GYSISFGSLA

¹⁶⁰

VAILIIGYFR

¹⁷⁰

RLHCTRNYIH

¹⁸⁰

MHLFVSFMLR

¹⁹⁰

ATSIFVKDRV

²⁰⁰

VHAHIGVKEL

²¹⁰

ESQYIGCKIA

²³⁹

VVMFIYFLAT

²⁴⁹

NYYWILVEGL

²⁵⁹

YLHNLIFVAF

²⁶⁹

FSDTKYLWGF

²⁷⁹

ILIGWGFPAA

²⁸⁹

FVAAWAVARA

²⁹⁹

TLADARCWEL

³⁰⁹

SAGDIKWIYQ

³¹⁹

APILAAIGLN

³²⁹

FILFLNTVRV

³³⁹

LATKIWETDT

³⁵⁴

RKQYRKLAKS

³⁶⁴

TLVLVLVFGV

³⁷⁴

HYIVFVCLPG

³⁸⁸

LGWEIRMHCE

³⁹⁸

LFFNSFQGFF

⁴⁰⁸

VSIIYCYCNG

⁴¹⁸

EVQAEVKKMW

⁴²⁸

SRWNLS

Residue

Distance (Å)

TYR178

3.660

MET181

3.435

HIS182

3.639

VAL185

4.014

LEU189

4.551

ILE234

3.726

LYS237

4.074

ILE238

4.409

VAL241

3.800

MET242

4.525

PHE246

4.633

TRP284

3.593

ALA288

4.841

Residue

Distance (Å)

ALA295

3.933

ALA299

4.086

LEU301

3.753

TRP307

3.701

ASP313

3.365

ILE314

4.251

TRP316

3.628

ILE317

3.711

ALA320

3.730

PRO321

3.843

LEU323

3.968

ALA324

3.853

GLY327

4.747

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Pathway Affiliation

Biological Network Descriptors

There is no similarity protein (E value < 0.005) for this target

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy

Degree	2	Degree centrality	2.15E-04	Betweenness centrality	0.00E+00
Closeness centrality	1.49E-01	Radiality	1.19E+01	Clustering coefficient	1.00E+00
Neighborhood connectivity	3.50E+00	Topological coefficient	7.00E-01	Eccentricity	14
Download	Click to Download the Full PPI Network of This Target

Co-Targets

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Co-Targets

Co-Targets Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 1 KEGG Pathways

Neuroactive ligand-receptor interaction

Reactome

[+] 2 Reactome Pathways

Class B/2 (Secretin family receptors)

G alpha (s) signalling events

WikiPathways

[+] 3 WikiPathways

GPCRs, Class B Secretin-like

GPCR ligand binding

GPCR downstream signaling

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Emerging therapies for the treatment of osteoporosis. J Midlife Health. 2013 Jul-Sep; 4(3): 147-152.

REF 2

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8299).

REF 3

ClinicalTrials.gov (NCT01343004) Study to Evaluate the Safety and Efficacy of BA058 (Abaloparatide) for Prevention of Fracture in Postmenopausal Women. U.S. National Institutes of Health.

REF 4

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015535)

REF 5

ClinicalTrials.gov (NCT02204579) A Study to Determine the Effects of NPSP795 on the Calcium-sensing Receptor in Subjects With Autosomal Dominant Hypocalcemia as Measured by PTH Levels and Blood Calcium Concentrations. U.S. National Institutes of Health.

REF 6

Pharmacokinetics of oral recombinant human parathyroid hormone [rhPTH(1-31)NH in postmenopausal women with osteoporosis. Clin Pharmacokinet. 2013 Nov;52(11):995-1004.

REF 7

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800019469)

REF 8

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007620)

REF 9

Comparison of bone formation responses to parathyroid hormone(1-34), (1-31), and (2-34) in mice. Bone. 2000 Oct;27(4):471-8.

REF 10

REF 11

Parathyroid hormone for the treatment of osteoporosis: a systematic review. CMAJ. 2006 July 4; 175(1): 52-59.

REF 12

Differential effects of intermittent PTH(1-34) and PTH(7-34) on bone microarchitecture and aortic calcification in experimental renal failure. Bone. 2008 Dec;43(6):1022-30.

REF 13

Quantitative cell membrane-based radioligand binding assays for parathyroid hormone receptors. J Pharmacol Toxicol Methods. 1999 Apr-Jun;41(2-3):83-90.

REF 14

The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.

REF 15

Long-term therapy of ovariectomy-induced osteopenia with parathyroid hormone analog SDZ PTS 893 and bone maintenance in retired breeder rats. Bone. 1999 Nov;25(5):561-9.

REF 16

Molecular insights into differentiated ligand recognition of the human parathyroid hormone receptor 2. Proc Natl Acad Sci U S A. 2021 Aug 10;118(32):e2101279118.

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