Target Information
| Target General Information | Top | |||||
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| Target ID |
T99041
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| Target Name |
HUMAN dipeptidyl peptidase 4 (DPP-4)
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| Synonyms |
Tcell activation antigen CD26; TP103; T-cell activation antigen CD26; Dipeptidyl peptidase IV; Dipeptidyl peptidase 4 soluble form; DPP-IV; DPP IV; DPP 4; CD26; Adenosine deaminase complexing protein-2; Adenosine deaminase complexing protein 2; ADCP2; ADCP-2; ADABP
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| Gene Name |
DPP4
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| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Type 2 diabetes mellitus [ICD-11: 5A11] | |||||
| Function |
Acts as a positive regulator of T-cell coactivation, by binding at least ADA, CAV1, IGF2R, and PTPRC. Its binding to CAV1 and CARD11 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner. Its interaction with ADA also regulates lymphocyte-epithelial cell adhesion. In association with FAP is involved in the pericellular proteolysis of the extracellular matrix (ECM), the migration and invasion of endothelial cells into the ECM. May be involved in the promotion of lymphatic endothelial cells adhesion, migration and tube formation. When overexpressed, enhanced cell proliferation, a process inhibited by GPC3. Acts also as a serine exopeptidase with a dipeptidyl peptidase activity that regulates various physiological processes by cleaving peptides in the circulation, including many chemokines, mitogenic growth factors, neuropeptides and peptide hormones. Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline. Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.14.5
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| Sequence |
MKTPWKVLLGLLGAAALVTIITVPVVLLNKGTDDATADSRKTYTLTDYLKNTYRLKLYSL
RWISDHEYLYKQENNILVFNAEYGNSSVFLENSTFDEFGHSINDYSISPDGQFILLEYNY VKQWRHSYTASYDIYDLNKRQLITEERIPNNTQWVTWSPVGHKLAYVWNNDIYVKIEPNL PSYRITWTGKEDIIYNGITDWVYEEEVFSAYSALWWSPNGTFLAYAQFNDTEVPLIEYSF YSDESLQYPKTVRVPYPKAGAVNPTVKFFVVNTDSLSSVTNATSIQITAPASMLIGDHYL CDVTWATQERISLQWLRRIQNYSVMDICDYDESSGRWNCLVARQHIEMSTTGWVGRFRPS EPHFTLDGNSFYKIISNEEGYRHICYFQIDKKDCTFITKGTWEVIGIEALTSDYLYYISN EYKGMPGGRNLYKIQLSDYTKVTCLSCELNPERCQYYSVSFSKEAKYYQLRCSGPGLPLY TLHSSVNDKGLRVLEDNSALDKMLQNVQMPSKKLDFIILNETKFWYQMILPPHFDKSKKY PLLLDVYAGPCSQKADTVFRLNWATYLASTENIIVASFDGRGSGYQGDKIMHAINRRLGT FEVEDQIEAARQFSKMGFVDNKRIAIWGWSYGGYVTSMVLGSGSGVFKCGIAVAPVSRWE YYDSVYTERYMGLPTPEDNLDHYRNSTVMSRAENFKQVEYLLIHGTADDNVHFQQSAQIS KALVDVGVDFQAMWYTDEDHGIASSTAHQHIYTHMSHFIKQCFSLP Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Drugs in Phase 3 Trial | [+] 1 | + | ||||
| 1 | Linagliptin | Drug Info | Approved | Type 2 diabetes | [2] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | Linagliptin | Drug Info | [3], [4] | |||
| Blocker | [+] 1 Blocker drugs | + | ||||
| 1 | YS110 mAb clone | Drug Info | [5], [6] | |||
| 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: Alogliptin | Ligand Info | |||||
| Structure Description | Crystal structure of dipeptidyl peptidase IV in complex with TAK-322 | PDB:3G0B | ||||
| Method | X-ray diffraction | Resolution | 2.25 Å | Mutation | No | [7] |
| PDB Sequence |
RKTYTLTDYL
49 KNTYRLKLYS59 LRWISDHEYL69 YKQENNILVF79 NAEYGNSSVF89 LENSTFDEFG 99 HSINDYSISP109 DGQFILLEYN119 YVKQWRHSYT129 ASYDIYDLNK139 RQLITEERIP 149 NNTQWVTWSP159 VGHKLAYVWN169 NDIYVKIEPN179 LPSYRITWTG189 KEDIIYNGIT 199 DWVYEEEVFS209 AYSALWWSPN219 GTFLAYAQFN229 DTEVPLIEYS239 FYSDESLQYP 249 KTVRVPYPKA259 GAVNPTVKFF269 VVNTDSLSSV279 TNATSIQITA289 PASMLIGDHY 299 LCDVTWATQE309 RISLQWLRRI319 QNYSVMDICD329 YDESSGRWNC339 LVARQHIEMS 349 TTGWVGRFRP359 SEPHFTLDGN369 SFYKIISNEE379 GYRHICYFQI389 DKKDCTFITK 399 GTWEVIGIEA409 LTSDYLYYIS419 NEYKGMPGGR429 NLYKIQLSDY439 TKVTCLSCEL 449 NPERCQYYSV459 SFSKEAKYYQ469 LRCSGPGLPL479 YTLHSSVNDK489 GLRVLEDNSA 499 LDKMLQNVQM509 PSKKLDFIIL519 NETKFWYQMI529 LPPHFDKSKK539 YPLLLDVYAG 549 PCSQKADTVF559 RLNWATYLAS569 TENIIVASFD579 GRGSGYQGDK589 IMHAINRRLG 599 TFEVEDQIEA609 ARQFSKMGFV619 DNKRIAIWGW629 SYGGYVTSMV639 LGSGSGVFKC 649 GIAVAPVSRW659 EYYDSVYTER669 YMGLPTPEDN679 LDHYRNSTVM689 SRAENFKQVE 699 YLLIHGTADD709 NVHFQQSAQI719 SKALVDVGVD729 FQAMWYTDED739 HGIASSTAHQ 749 HIYTHMSHFI759 KQCFSLP
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| Ligand Name: Linagliptin | Ligand Info | |||||
| Structure Description | Crystal structure of complex of human DPP4 and inhibitor | PDB:2RGU | ||||
| Method | X-ray diffraction | Resolution | 2.60 Å | Mutation | No | [8] |
| PDB Sequence |
SRKTYTLTDY
48 LKNTYRLKLY58 SLRWISDHEY68 LYKQENNILV78 FNAEYGNSSV88 FLENSTFDEF 98 GHSINDYSIS108 PDGQFILLEY118 NYVKQWRHSY128 TASYDIYDLN138 KRQLITEERI 148 PNNTQWVTWS158 PVGHKLAYVW168 NNDIYVKIEP178 NLPSYRITWT188 GKEDIIYNGI 198 TDWVYEEEVF208 SAYSALWWSP218 NGTFLAYAQF228 NDTEVPLIEY238 SFYSDESLQY 248 PKTVRVPYPK258 AGAVNPTVKF268 FVVNTDSLSS278 VTNATSIQIT288 APASMLIGDH 298 YLCDVTWATQ308 ERISLQWLRR318 IQNYSVMDIC328 DYDESSGRWN338 CLVARQHIEM 348 STTGWVGRFR358 PSEPHFTLDG368 NSFYKIISNE378 EGYRHICYFQ388 IDKKDCTFIT 398 KGTWEVIGIE408 ALTSDYLYYI418 SNEYKGMPGG428 RNLYKIQLSD438 YTKVTCLSCE 448 LNPERCQYYS458 VSFSKEAKYY468 QLRCSGPGLP478 LYTLHSSVND488 KGLRVLEDNS 498 ALDKMLQNVQ508 MPSKKLDFII518 LNETKFWYQM528 ILPPHFDKSK538 KYPLLLDVYA 548 GPCSQKADTV558 FRLNWATYLA568 STENIIVASF578 DGRGSGYQGD588 KIMHAINRRL 598 GTFEVEDQIE608 AARQFSKMGF618 VDNKRIAIWG628 WSYGGYVTSM638 VLGSGSGVFK 648 CGIAVAPVSR658 WEYYDSVYTE668 RYMGLPTPED678 NLDHYRNSTV688 MSRAENFKQV 698 EYLLIHGTAD708 DNVHFQQSAQ718 ISKALVDVGV728 DFQAMWYTDE738 DHGIASSTAH 748 QHIYTHMSHF758 IKQCFSLP
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| 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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There is no similarity protein (E value < 0.005) for this target
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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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| Protein digestion and absorption | hsa04974 | Affiliated Target |
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| Class: Organismal Systems => Digestive system | Pathway Hierarchy | ||
| Degree | 14 | Degree centrality | 1.50E-03 | Betweenness centrality | 2.15E-03 |
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| Closeness centrality | 2.25E-01 | Radiality | 1.40E+01 | Clustering coefficient | 7.69E-02 |
| Neighborhood connectivity | 2.59E+01 | Topological coefficient | 9.21E-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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| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| References | Top | |||||
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| REF 1 | In-vitro renal epithelial cell infection reveals a viral kidney tropism as a potential mechanism for acute renal failure during Middle East Respira... Virol J. 2013 Dec 23;10:359. | |||||
| REF 2 | FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (NDA) 208026 | |||||
| REF 3 | DPP4 inhibition: preventing SARS-CoV-2 infection and/or progression of COVID-19 Diabetes Metab Res Rev. 2020 Apr 26. | |||||
| REF 4 | Effects of Dipeptidyl Peptidase 4 Inhibition on Inflammation in Atherosclerosis: A 18 F-fluorodeoxyglucose Study of a Mouse Model of Atherosclerosis and Type 2 DiabetesAtherosclerosis. 2020 Apr 10. pii: S0021-9150(20)30194-5. | |||||
| REF 5 | Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47. | |||||
| REF 6 | Inhibition of Middle East respiratory syndrome coronavirus infection by anti-CD26 monoclonal antibody. J Virol. 2013 Dec;87(24):13892-9. | |||||
| REF 7 | Design and synthesis of pyrimidinone and pyrimidinedione inhibitors of dipeptidyl peptidase IV. J Med Chem. 2011 Jan 27;54(2):510-24. | |||||
| REF 8 | 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, sele... J Med Chem. 2007 Dec 27;50(26):6450-3. | |||||
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