Target Information
| Target General Information | Top | |||||
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| Target ID |
T81900
(Former ID: TTDS00134)
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| Target Name |
Insulin-degrading enzyme (IDE)
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| Synonyms |
Insulysin; Insulinase; Insulin protease; Abeta-degrading protease
Click to Show/Hide
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| Gene Name |
IDE
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Skin and skin-structure infection [ICD-11: 1F28-1G0Z] | |||||
| Function |
Substrate binding induces important conformation changes, making it possible to bind and degrade larger substrates, such as insulin. Contributes to the regulation of peptide hormone signaling cascades and regulation of blood glucose homeostasis via its role in the degradation of insulin, glucagon and IAPP. Plays a role in the degradation and clearance of APP-derived amyloidogenic peptides that are secreted by neurons and microglia. Involved in antigen processing. Produces both the N terminus and the C terminus of MAGEA3-derived antigenic peptide (EVDPIGHLY) that is presented to cytotoxic T lymphocytes by MHC class I. Plays a role in the cellular breakdown of insulin, APP peptides, IAPP peptides, glucagon, bradykinin, kallidin and other peptides, and thereby plays a role in intercellular peptide signaling.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.24.56
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| Sequence |
MRYRLAWLLHPALPSTFRSVLGARLPPPERLCGFQKKTYSKMNNPAIKRIGNHITKSPED
KREYRGLELANGIKVLLISDPTTDKSSAALDVHIGSLSDPPNIAGLSHFCEHMLFLGTKK YPKENEYSQFLSEHAGSSNAFTSGEHTNYYFDVSHEHLEGALDRFAQFFLCPLFDESCKD REVNAVDSEHEKNVMNDAWRLFQLEKATGNPKHPFSKFGTGNKYTLETRPNQEGIDVRQE LLKFHSAYYSSNLMAVCVLGRESLDDLTNLVVKLFSEVENKNVPLPEFPEHPFQEEHLKQ LYKIVPIKDIRNLYVTFPIPDLQKYYKSNPGHYLGHLIGHEGPGSLLSELKSKGWVNTLV GGQKEGARGFMFFIINVDLTEEGLLHVEDIILHMFQYIQKLRAEGPQEWVFQECKDLNAV AFRFKDKERPRGYTSKIAGILHYYPLEEVLTAEYLLEEFRPDLIEMVLDKLRPENVRVAI VSKSFEGKTDRTEEWYGTQYKQEAIPDEVIKKWQNADLNGKFKLPTKNEFIPTNFEILPL EKEATPYPALIKDTAMSKLWFKQDDKFFLPKACLNFEFFSPFAYVDPLHCNMAYLYLELL KDSLNEYAYAAELAGLSYDLQNTIYGMYLSVKGYNDKQPILLKKIIEKMATFEIDEKRFE IIKEAYMRSLNNFRAEQPHQHAMYYLRLLMTEVAWTKDELKEALDDVTLPRLKAFIPQLL SRLHIEALLHGNITKQAALGIMQMVEDTLIEHAHTKPLLPSQLVRYREVQLPDRGWFVYQ QRNEVHNNCGIEIYYQTDMQSTSENMFLELFCQIISEPCFNTLRTKEQLGYIVFSGPRRA NGIQGLRFIIQSEKPPHYLESRVEAFLITMEKSIEDMTEEAFQKHIQALAIRRLDKPKKL SAECAKYWGEIISQQYNFDRDNTEVAYLKTLTKEDIIKFYKEMLAVDAPRRHKVSVHVLA REMDSCPVVGEFPCQNDINLSQAPALPQPEVIQNMTEFKRGLPLFPLVKPHINFMAAKL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T24YWQ | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Bacitracin | Drug Info | Approved | Skin infection | [2], [3] | |
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | PRO-001 | Drug Info | Phase 2 | Retinitis pigmentosa | [4] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 5 Inhibitor drugs | + | ||||
| 1 | Bacitracin | Drug Info | [1] | |||
| 2 | GNF-PF-4478 | Drug Info | [6] | |||
| 3 | NTE-1 | Drug Info | [7] | |||
| 4 | NTE-2 | Drug Info | [7] | |||
| 5 | quinoline 2 | Drug Info | [7] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | PRO-001 | Drug Info | [5] | |||
| 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: NTE-2 | Ligand Info | |||||
| Structure Description | Crystal structure of insulin degrading enzyme complexed with inhibitor | PDB:4PFC | ||||
| Method | X-ray diffraction | Resolution | 2.21 Å | Mutation | Yes | [7] |
| PDB Sequence |
NNPAIKRIGN
52 HITKSPEDKR62 EYRGLELANG72 IKVLLISDPT82 TDKSSAALDV92 HIGSLSDPPN 102 IAGLSHFLQH112 MLFLGTKKYP122 KENEYSQFLS132 EHAGSSNAFT142 SGEHTNYYFD 152 VSHEHLEGAL162 DRFAQFFLSP172 LFDESAKDRE182 VNAVDSEHEK192 NVMNDAWRLF 202 QLEKATGNPK212 HPFSKFGTGN222 KYTLETRPNQ232 EGIDVRQELL242 KFHSAYYSSN 252 LMAVVVLGRE262 SLDDLTNLVV272 KLFSEVENKN282 VPLPEFPEHP292 FQEEHLKQLY 302 KIVPIKDIRN312 LYVTFPIPDL322 QKYYKSNPGH332 YLGHLIGHEG342 PGSLLSELKS 352 KGWVNTLVGG362 QKEGARGFMF372 FIINVDLTEE382 GLLHVEDIIL392 HMFQYIQKLR 402 AEGPQEWVFQ412 ELKDLNAVAF422 RFKDKERPRG432 YTSKIAGILH442 YYPLEEVLTA 452 EYLLEEFRPD462 LIEMVLDKLR472 PENVRVAIVS482 KSFEGKTDRT492 EEWYGTQYKQ 502 EAIPDEVIKK512 WQNADLNGKF522 KLPTKNEFIP532 TNFEILPLEK542 EATPYPALIK 552 DTAMSKLWFK562 QDDKFFLPKA572 NLNFEFFSPF582 AYVDPLHSNM592 AYLYLELLKD 602 SLNEYAYAAE612 LAGLSYDLQN622 TIYGMYLSVK632 GYNDKQPILL642 KKIIEKMATF 652 EIDEKRFEII662 KEAYMRSLNN672 FRAEQPHQHA682 MYYLRLLMTE692 VAWTKDELKE 702 ALDDVTLPRL712 KAFIPQLLSR722 LHIEALLHGN732 ITKQAALGIM742 QMVEDTLIEH 752 AHTKPLLPSQ762 LVRYREVQLP772 DRGWFVYQQR782 NEVHNNSGIE792 IYYQTDMQST 802 SENMFLELFA812 QIISEPAFNT822 LRTKEQLGYI832 VFSGPRRANG842 IQGLRFIIQS 852 EKPPHYLESR862 VEAFLITMEK872 SIEDMTEEAF882 QKHIQALAIR892 RLDKPKKLSA 902 ESAKYWGEII912 SQQYNFDRDN922 TEVAYLKTLT932 KEDIIKFYKE942 MLAVDAPRRH 952 KVSVHVLARE962 MDSDINLSQA983 PALPQPEVIQ993 NMTEFKRGLP1003 LFPLVKPHI |
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ALA198
4.023
LEU201
3.382
PHE202
3.441
LEU204
3.975
GLU205
2.971
THR208
3.528
TYR302
3.240
ILE304
3.776
TYR314
3.541
THR316
3.691
HIS332
3.346
GLY335
3.986
HIS336
3.636
GLY339
2.772
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| Ligand Name: Quinoline 2 | Ligand Info | |||||
| Structure Description | Crystal structure of insulin degrading enzyme complexed with inhibitor tert-butyl [(2S)-2-(2,5-difluorophenyl)-3-(quinolin-3-yl)propyl]carbamate | PDB:4PES | ||||
| Method | X-ray diffraction | Resolution | 2.21 Å | Mutation | Yes | [8] |
| PDB Sequence |
NPAIKRIGNH
53 ITKSPEDKRE63 YRGLELANGI73 KVLLISDPTT83 DKSSAALDVH93 IGSLSDPPNI 103 AGLSHFLQHM113 LFLGTKKYPK123 ENEYSQFLSE133 HAGSSNAFTS143 GEHTNYYFDV 153 SHEHLEGALD163 RFAQFFLSPL173 FDESAKDREV183 NAVDSEHEKN193 VMNDAWRLFQ 203 LEKATGNPKH213 PFSKFGTGNK223 YTLETRPNQE233 GIDVRQELLK243 FHSAYYSSNL 253 MAVVVLGRES263 LDDLTNLVVK273 LFSEVENKNV283 PLPEFPEHPF293 QEEHLKQLYK 303 IVPIKDIRNL313 YVTFPIPDLQ323 KYYKSNPGHY333 LGHLIGHEGP343 GSLLSELKSK 353 GWVNTLVGGQ363 KEGARGFMFF373 IINVDLTEEG383 LLHVEDIILH393 MFQYIQKLRA 403 EGPQEWVFQE413 LKDLNAVAFR423 FKDKERPRGY433 TSKIAGILHY443 YPLEEVLTAE 453 YLLEEFRPDL463 IEMVLDKLRP473 ENVRVAIVSK483 SFEGKTDRTE493 EWYGTQYKQE 503 AIPDEVIKKW513 QNADLNGKFK523 LPTKNEFIPT533 NFEILPLEKE543 ATPYPALIKD 553 TAMSKLWFKQ563 DDKFFLPKAN573 LNFEFFSPFA583 YVDPLHSNMA593 YLYLELLKDS 603 LNEYAYAAEL613 AGLSYDLQNT623 IYGMYLSVKG633 YNDKQPILLK643 KIIEKMATFE 653 IDEKRFEIIK663 EAYMRSLNNF673 RAEQPHQHAM683 YYLRLLMTEV693 AWTKDELKEA 703 LDDVTLPRLK713 AFIPQLLSRL723 HIEALLHGNI733 TKQAALGIMQ743 MVEDTLIEHA 753 HTKPLLPSQL763 VRYREVQLPD773 RGWFVYQQRN783 EVHNNSGIEI793 YYQTDMQSTS 803 ENMFLELFAQ813 IISEPAFNTL823 RTKEQLGYIV833 FSGPRRANGI843 QGLRFIIQSE 853 KPPHYLESRV863 EAFLITMEKS873 IEDMTEEAFQ883 KHIQALAIRR893 LDKPKKLSAE 903 SAKYWGEIIS913 QQYNFDRDNT923 EVAYLKTLTK933 EDIIKFYKEM943 LAVDAPRRHK 953 VSVHVLAREM963 DSLSQAPALP987 QPEVIQNMTE997 FKRGLPLFPL1007 VKPHI |
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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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| Virion - Herpesvirus | hsa03266 | Affiliated Target |
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| Class: Genetic Information Processing => Information processing in viruses | Pathway Hierarchy | ||
| Degree | 6 | Degree centrality | 6.45E-04 | Betweenness centrality | 8.78E-04 |
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| Closeness centrality | 2.27E-01 | Radiality | 1.40E+01 | Clustering coefficient | 1.33E-01 |
| Neighborhood connectivity | 4.53E+01 | Topological coefficient | 1.75E-01 | 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 Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Alzheimer's disease | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Alzheimers Disease | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Brain insulin impairs amyloid-beta(1-40) clearance from the brain. J Neurosci. 2004 Oct 27;24(43):9632-7. | |||||
| REF 2 | Has nature already identified all useful antibacterial targets Curr Opin Microbiol. 2008 Oct;11(5):387-92. | |||||
| REF 3 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 4 | ClinicalTrials.gov (NCT02520583) The Effects of Probiotic Supplementation on Markers of Muscle Damage and Performance Following Exercise Induced Muscle Damage. | |||||
| REF 5 | 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: 2371). | |||||
| REF 6 | In silico identification and biochemical evaluation of novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2). Bioorg Med Chem Lett. 2010 Dec 15;20(24):7331-6. | |||||
| REF 7 | Dual Exosite-binding Inhibitors of Insulin-degrading Enzyme Challenge Its Role as the Primary Mediator of Insulin Clearance in Vivo. J Biol Chem. 2015 Aug 14;290(33):20044-59. | |||||
| REF 8 | Crystal structure of IDE complexed with an inhibitor | |||||
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