Target Information
| Target General Information | Top | |||||
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| Target ID |
T60213
(Former ID: TTDI01817)
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| Target Name |
Bone morphogenetic protein receptor (BMPR2)
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| Synonyms |
PPH1; Bone morphogenetic protein receptor type-2; Bone morphogenetic protein receptor type II; BMPR-II; BMPR-2; BMP type-2 receptor; BMP type II receptor
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| Gene Name |
BMPR2
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| Target Type |
Literature-reported target
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[1] | ||||
| Disease | [+] 4 Target-related Diseases | + | ||||
| 1 | Joint derangement [ICD-11: FA34] | |||||
| 2 | Prostate cancer [ICD-11: 2C82] | |||||
| 3 | Urinary system disease [ICD-11: GC2Z] | |||||
| 4 | Urinary/pelvic organs injury [ICD-11: NB92] | |||||
| Function |
Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Binds to BMP7, BMP2 and, less efficiently, BMP4. Binding is weak but enhanced by the presence of type I receptors for BMPs. Mediates induction of adipogenesis by GDF6. On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.30
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| Sequence |
MTSSLQRPWRVPWLPWTILLVSTAAASQNQERLCAFKDPYQQDLGIGESRISHENGTILC
SKGSTCYGLWEKSKGDINLVKQGCWSHIGDPQECHYEECVVTTTPPSIQNGTYRFCCCST DLCNVNFTENFPPPDTTPLSPPHSFNRDETIIIALASVSVLAVLIVALCFGYRMLTGDRK QGLHSMNMMEAAASEPSLDLDNLKLLELIGRGRYGAVYKGSLDERPVAVKVFSFANRQNF INEKNIYRVPLMEHDNIARFIVGDERVTADGRMEYLLVMEYYPNGSLCKYLSLHTSDWVS SCRLAHSVTRGLAYLHTELPRGDHYKPAISHRDLNSRNVLVKNDGTCVISDFGLSMRLTG NRLVRPGEEDNAAISEVGTIRYMAPEVLEGAVNLRDCESALKQVDMYALGLIYWEIFMRC TDLFPGESVPEYQMAFQTEVGNHPTFEDMQVLVSREKQRPKFPEAWKENSLAVRSLKETI EDCWDQDAEARLTAQCAEERMAELMMIWERNKSVSPTVNPMSTAMQNERNLSHNRRVPKI GPYPDYSSSSYIEDSIHHTDSIVKNISSEHSMSSTPLTIGEKNRNSINYERQQAQARIPS PETSVTSLSTNTTTTNTTGLTPSTGMTTISEMPYPDETNLHTTNVAQSIGPTPVCLQLTE EDLETNKLDPKEVDKNLKESSDENLMEHSLKQFSGPDPLSSTSSSLLYPLIKLAVEATGQ QDFTQTANGQACLIPDVLPTQIYPLPKQQNLPKRPTSLPLNTKNSTKEPRLKFGSKHKSN LKQVETGVAKMNTINAAEPHVVTVTMNGVAGRNHSVNSHAATTQYANGTVLSGQTTNIVT HRAQEMLQNQFIGEDTRLNINSSPDEHEPLLRREQQAGHDEGVLDRLVDRRERPLEGGRT NSNNNNSNPCSEQDVLAQGVPSTAADPGPSKPRRAQRPNSLDLSATNVLDGSSIQIGEST QDGKSGSGEKIKKRVKTPYSLKRWRPSTWVISTESLDCEVNNNGSNRAVHSKSSTAVYLA EGGTATTMVSKDIGMNCL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T10IWJ | |||||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: adenosine diphosphate | Ligand Info | |||||
| Structure Description | Crystal structure of the kinase domain of BMPR2-D485G | PDB:6UNP | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | Yes | [4] |
| PDB Sequence |
DLDNLKLLEL
208 IGRGRYGAVY218 KGSLDERPVA228 VKVFSFANRQ238 NFINEKNIYR248 VPLMEHDNIA 258 RFIVGDERVT268 ADGRMEYLLV278 MEYYPNGSLK289 YLSLHTSDWV299 SSCRLAHSVT 309 RGLAYLHTEL319 PRGDHYKPAI329 SHRDLNSRNV339 LVKNDGTCVI349 SDFGLSMRLT 359 GNRLVRPEVG378 TIRYMAPEVL388 EGAVNLRDES399 ALKQVDMYAL409 GLIYWEIFMR 419 CTDLFPGESV429 PEYQMAFQTE439 VGNHPTFEDM449 QVLVSREKQR459 PKFPEAWKEN 469 SLAVRSLKET479 IEDCWGQDAE489 ARLTAQAEER500 MAELMMIWE
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ILE209
3.628
GLY210
3.517
ARG211
3.868
GLY212
3.108
ARG213
3.233
TYR214
2.787
GLY215
2.799
VAL217
3.520
ALA228
3.423
LYS230
2.729
GLU243
4.712
MET279
3.314
GLU280
2.821
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: S-(Dimethylarsenic)Cysteine | Ligand Info | |||||
| Structure Description | Crystal structure of the kinase domain of BMPR2-D485G | PDB:6UNP | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | Yes | [4] |
| PDB Sequence |
DLDNLKLLEL
208 IGRGRYGAVY218 KGSLDERPVA228 VKVFSFANRQ238 NFINEKNIYR248 VPLMEHDNIA 258 RFIVGDERVT268 ADGRMEYLLV278 MEYYPNGSLK289 YLSLHTSDWV299 SSCRLAHSVT 309 RGLAYLHTEL319 PRGDHYKPAI329 SHRDLNSRNV339 LVKNDGTCVI349 SDFGLSMRLT 359 GNRLVRPEVG378 TIRYMAPEVL388 EGAVNLRDES399 ALKQVDMYAL409 GLIYWEIFMR 419 CTDLFPGESV429 PEYQMAFQTE439 VGNHPTFEDM449 QVLVSREKQR459 PKFPEAWKEN 469 SLAVRSLKET479 IEDCWGQDAE489 ARLTAQAEER500 MAELMMIWE
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SER286
3.148
LEU287
1.335
LYS289
1.320
TYR290
3.274
LEU291
3.393
SER292
2.992
SER336
2.895
ARG337
3.739
VAL339
4.998
MET356
4.763
ARG357
4.523
LEU358
4.053
VAL364
4.327
PRO366
4.348
ASN393
4.074
LEU394
3.339
ARG395
3.368
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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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 Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
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 Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Cytokine-cytokine receptor interaction | hsa04060 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| TGF-beta signaling pathway | hsa04350 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Axon guidance | hsa04360 | Affiliated Target |
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| Class: Organismal Systems => Development and regeneration | Pathway Hierarchy | ||
| Hippo signaling pathway | hsa04390 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Signaling pathways regulating pluripotency of stem cells | hsa04550 | Affiliated Target |
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| Class: Cellular Processes => Cellular community - eukaryotes | Pathway Hierarchy | ||
| Degree | 29 | Degree centrality | 3.12E-03 | Betweenness centrality | 1.60E-03 |
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| Closeness centrality | 2.23E-01 | Radiality | 1.39E+01 | Clustering coefficient | 2.54E-01 |
| Neighborhood connectivity | 1.76E+01 | Topological coefficient | 8.79E-02 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 4 KEGG Pathways | + | ||||
| 1 | Cytokine-cytokine receptor interaction | |||||
| 2 | TGF-beta signaling pathway | |||||
| 3 | Hippo signaling pathway | |||||
| 4 | Signaling pathways regulating pluripotency of stem cells | |||||
| WikiPathways | [+] 10 WikiPathways | + | ||||
| 1 | Endochondral Ossification | |||||
| 2 | Ectoderm Differentiation | |||||
| 3 | Mesodermal Commitment Pathway | |||||
| 4 | Endoderm Differentiation | |||||
| 5 | Hair Follicle Development: Cytodifferentiation (Part 3 of 3) | |||||
| 6 | Hair Follicle Development: Induction (Part 1 of 3) | |||||
| 7 | Signaling by BMP | |||||
| 8 | Integrated Breast Cancer Pathway | |||||
| 9 | Heart Development | |||||
| 10 | BMP Signalling and Regulation | |||||
| References | Top | |||||
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| REF 1 | 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. (Target id: 1794). | |||||
| REF 2 | Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants. J Med Chem. 2014 Oct 9;57(19):7900-15. | |||||
| REF 3 | Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of dorsomorphin: the discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe. Bioorg Med Chem Lett. 2013 Jun 1;23(11):3248-52. | |||||
| REF 4 | Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization. Nat Commun. 2021 Aug 16;12(1):4950. | |||||
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