Target Information
| Target General Information | Top | |||||
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| Target ID |
T11283
(Former ID: TTDR00663)
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| Target Name |
Mitochondrial matrix protein P1 (HSPD1)
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| Synonyms |
P60 lymphocyte protein; HuCHA60; Hsp60; Heat shock protein 60; HSP-60; Chaperonin 60; CPN60; 60 kDa heat shock protein, mitochondrial; 60 kDa chaperonin
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| Gene Name |
HSPD1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Diabetes mellitus [ICD-11: 5A10] | |||||
| Function |
Together with Hsp10, facilitates the correct folding of imported proteins. May also prevent misfolding and promote the refolding and proper assembly of unfolded polypeptides generated under stress conditions in the mitochondrial matrix. The functional units of these chaperonins consist of heptameric rings of the large subunit Hsp60, which function as a back-to-back double ring. In a cyclic reaction, Hsp60 ring complexes bind one unfolded substrate protein per ring, followed by the binding of ATP and association with 2 heptameric rings of the co-chaperonin Hsp10. This leads to sequestration of the substrate protein in the inner cavity of Hsp60 where, for a certain period of time, it can fold undisturbed by other cell components. Synchronous hydrolysis of ATP in all Hsp60 subunits results in the dissociation of the chaperonin rings and the release of ADP and the folded substrate protein. Chaperonin implicated in mitochondrial protein import and macromolecular assembly.
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| BioChemical Class |
Chaperonin ATPase
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| UniProt ID | ||||||
| EC Number |
EC 5.6.1.7
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| Sequence |
MLRLPTVFRQMRPVSRVLAPHLTRAYAKDVKFGADARALMLQGVDLLADAVAVTMGPKGR
TVIIEQSWGSPKVTKDGVTVAKSIDLKDKYKNIGAKLVQDVANNTNEEAGDGTTTATVLA RSIAKEGFEKISKGANPVEIRRGVMLAVDAVIAELKKQSKPVTTPEEIAQVATISANGDK EIGNIISDAMKKVGRKGVITVKDGKTLNDELEIIEGMKFDRGYISPYFINTSKGQKCEFQ DAYVLLSEKKISSIQSIVPALEIANAHRKPLVIIAEDVDGEALSTLVLNRLKVGLQVVAV KAPGFGDNRKNQLKDMAIATGGAVFGEEGLTLNLEDVQPHDLGKVGEVIVTKDDAMLLKG KGDKAQIEKRIQEIIEQLDVTTSEYEKEKLNERLAKLSDGVAVLKVGGTSDVEVNEKKDR VTDALNATRAAVEEGIVLGGGCALLRCIPALDSLTPANEDQKIGIEIIKRTLKIPAMTIA KNAGVEGSLIVEKIMQSSSEVGYDAMAGDFVNMVEKGIIDPTKVVRTALLDAAGVASLLT TAEVVVTEIPKEEKDPGMGAMGGMGGGMGGGMF Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T46BOC | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | DiaPep-277 | Drug Info | Phase 3 | Autoimmune diabetes | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | DiaPep-277 | Drug Info | [1], [3] | |||
| 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 | ADP-bound human mitochondrial Hsp60-Hsp10 football complex | PDB:6MRC | ||||
| Method | Electron microscopy | Resolution | 3.08 Å | Mutation | No | [4] |
| PDB Sequence |
GSAKDVKFGA
10 DARALMLQGV20 DLLADAVAVT30 MGPKGRTVII40 EQSWGSPKVT50 KDGVTVAKSI 60 DLKDKYKNIG70 AKLVQDVANN80 TNEEAGDGTT90 TATVLARSIA100 KEGFEKISKG 110 ANPVEIRRGV120 MLAVDAVIAE130 LKKQSKPVTT140 PEEIAQVATI150 SANGDKEIGN 160 IISDAMKKVG170 RKGVITVKDG180 KTLNDELEII190 EGMKFDRGYI200 SPYFINTSKG 210 QKCEFQDAYV220 LLSEKKISSI230 QSIVPALEIA240 NAHRKPLVII250 AEDVDGEALS 260 TLVLNRLKVG270 LQVVAVKAPG280 FGDNRKNQLK290 DMAIATGGAV300 FGEEGLTLNL 310 EDVQPHDLGK320 VGEVIVTKDD330 AMLLKGKGDK340 AQIEKRIQEI350 IEQLDVTTSE 360 YEKEKLNERL370 AKLSDGVAVL380 KVGGTSDVEV390 NEKKDRVTDA400 LNATRAAVEE 410 GIVLGGGCAL420 LRCIPALDSL430 TPANEDQKIG440 IEIIKRTLKI450 PAMTIAKNAG 460 VEGSLIVEKI470 MQSSSEVGYD480 AMAGDFVNMV490 EKGIIDPTKV500 VRTALLDAAG 510 VASLLTTAEV520 VVTEIPKE
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THR30
4.018
MET31
2.480
GLY32
1.710
PRO33
2.717
LYS51
3.265
GLY53
4.660
ASP87
2.680
GLY88
2.460
THR89
3.128
THR90
2.429
THR91
3.555
ILE150
2.895
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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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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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| RNA degradation | hsa03018 | Affiliated Target |
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| Class: Genetic Information Processing => Folding, sorting and degradation | Pathway Hierarchy | ||
| Degree | 25 | Degree centrality | 2.69E-03 | Betweenness centrality | 7.00E-03 |
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| Closeness centrality | 2.40E-01 | Radiality | 1.42E+01 | Clustering coefficient | 1.07E-01 |
| Neighborhood connectivity | 2.48E+01 | Topological coefficient | 6.48E-02 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| 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 | RNA degradation | |||||
| 2 | Type I diabetes mellitus | |||||
| 3 | Legionellosis | |||||
| 4 | Tuberculosis | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | TCR Signaling Pathway | |||||
| PID Pathway | [+] 2 PID Pathways | + | ||||
| 1 | Validated targets of C-MYC transcriptional activation | |||||
| 2 | Endogenous TLR signaling | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Mitochondrial protein import | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | SIDS Susceptibility Pathways | |||||
| 2 | Apoptosis-related network due to altered Notch3 in ovarian cancer | |||||
| References | Top | |||||
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| REF 1 | Therapy with the hsp60 peptide DiaPep277 in C-peptide positive type 1 diabetes patients. Diabetes Metab Res Rev. 2007 May;23(4):269-75. | |||||
| REF 2 | ClinicalTrials.gov (NCT01460251) OPen Label Study to Evaluate Long Term Treatment Effect of DiaPep277. U.S. National Institutes of Health. | |||||
| REF 3 | Immune modulation in type 1 diabetes mellitus using DiaPep277: a short review and update of recent clinical trial results. Diabetes Metab Res Rev. 2009 May;25(4):316-20. | |||||
| REF 4 | Structural basis for active single and double ring complexes in human mitochondrial Hsp60-Hsp10 chaperonin. Nat Commun. 2020 Apr 21;11(1):1916. | |||||
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