Target Information
| Target General Information | Top | |||||
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| Target ID |
T17967
(Former ID: TTDI02231)
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| Target Name |
Pyruvate dehydrogenase kinase 2 (PDHK2)
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| Synonyms |
PDKII; PDK2; PDH kinase 2; [Pyruvate dehydrogenase [lipoamide]] kinase isozyme 2, mitochondrial
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| Gene Name |
PDK2
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| Target Type |
Literature-reported target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Acute diabete complication [ICD-11: 5A2Y] | |||||
| Function |
Kinase that plays a key role in the regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism. Mediates cellular responses to insulin. Plays an important role in maintaining normal blood glucose levels and in metabolic adaptation to nutrient availability. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. Plays a role in the regulation of cell proliferation and in resistance to apoptosis under oxidative stress. Plays a role in p53/TP53-mediated apoptosis.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.2
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| Sequence |
MRWVWALLKNASLAGAPKYIEHFSKFSPSPLSMKQFLDFGSSNACEKTSFTFLRQELPVR
LANIMKEINLLPDRVLSTPSVQLVQSWYVQSLLDIMEFLDKDPEDHRTLSQFTDALVTIR NRHNDVVPTMAQGVLEYKDTYGDDPVSNQNIQYFLDRFYLSRISIRMLINQHTLIFDGST NPAHPKHIGSIDPNCNVSEVVKDAYDMAKLLCDKYYMASPDLEIQEINAANSKQPIHMVY VPSHLYHMLFELFKNAMRATVESHESSLILPPIKVMVALGEEDLSIKMSDRGGGVPLRKI ERLFSYMYSTAPTPQPGTGGTPLAGFGYGLPISRLYAKYFQGDLQLFSMEGFGTDAVIYL KALSTDSVERLPVYNKSAWRHYQTIQEAGDWCVPSTEPKNTSTYRVS 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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| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | AZD-7545 | Drug Info | Terminated | Diabetic complication | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | AZD-7545 | Drug Info | [1] | |||
| 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 triphosphate | Ligand Info | |||||
| Structure Description | crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands | PDB:2BU2 | ||||
| Method | X-ray diffraction | Resolution | 2.40 Å | Mutation | No | [3] |
| PDB Sequence |
GSAPKYIEHF
15 SKFSPSPLSM25 KQFLDFSNAC37 EKTSFTFLRQ47 ELPVRLANIM57 KEINLLPDRV 67 LSTPSVQLVQ77 SWYVQSLLDI87 MEFLDKDPED97 HRTLSQFTDA107 LVTIRNRHND 117 VVPTMAQGVL127 EYKDTYGDDP137 VSNQNIQYFL147 DRFYLSRISI157 RMLINQHTLI 167 FDPKHIGSID184 PNCNVSEVVK194 DAYDMAKLLC204 DKYYMASPDL214 EIQEINAANS 224 KQPIHMVYVP234 SHLYHMLFEL244 FKNAMRATVE254 SHESSLILPP264 IKVMVALGEE 274 DLSIKMSDRG284 GGVPLRKIER294 LFSYMYSTLA316 GFGYGLPISR326 LYAKYFQGDL 336 QLFSMEGFGT346 DAVIYLKALS356 TDSVERLPVY366 NKSAWRHYQT376 IQEAGDWCV |
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GLU243
3.577
LYS246
4.127
ASN247
3.008
ALA248
3.971
ARG250
3.223
ALA251
3.306
ASP282
2.898
GLY284
4.693
GLY286
4.304
VAL287
3.290
LEU295
2.986
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| Ligand Name: TF2 | Ligand Info | |||||
| Structure Description | crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands | PDB:2BU6 | ||||
| Method | X-ray diffraction | Resolution | 2.40 Å | Mutation | No | [3] |
| PDB Sequence |
GSAPKYIEHF
15 SKFSPSPLSM25 KQFLDFACEK39 TSFTFLRQEL49 PVRLANIMKE59 INLLPDRVLS 69 TPSVQLVQSW79 YVQSLLDIME89 FLDKDPEDHR99 TLSQFTDALV109 TIRNRHNDVV 119 PTMAQGVLEY129 KDTYGDDPVS139 NQNIQYFLDR149 FYLSRISIRM159 LINQHTLIFD 169 KHIGSIDPNC187 NVSEVVKDAY197 DMAKLLCDKY207 YMASPDLEIQ217 EINAANSKQP 227 IHMVYVPSHL237 YHMLFELFKN247 AMRATVESHE257 SSLILPPIKV267 MVALGEEDLS 277 IKMSDRGGGV287 PLRKIERLFS297 YMYSTAPGYG321 LPISRLYAKY331 FQGDLQLFSM 341 EGFGTDAVIY351 LKALSTDSVE361 RLPVYNKSAW371 RHYQTIQEAG381 DWCV |
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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).
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
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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| Degree | 5 | Degree centrality | 5.37E-04 | Betweenness centrality | 1.20E-03 |
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| Closeness centrality | 2.28E-01 | Radiality | 1.40E+01 | Clustering coefficient | 6.00E-01 |
| Neighborhood connectivity | 4.64E+01 | Topological coefficient | 2.42E-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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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Regulation of pyruvate dehydrogenase (PDH) complex | |||||
| References | Top | |||||
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| REF 1 | Recognition of the inner lipoyl-bearing domain of dihydrolipoyl transacetylase and of the blood glucose-lowering compound AZD7545 by pyruvate dehyd... Biochemistry. 2007 Jul 24;46(29):8592-602. | |||||
| REF 2 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800016834) | |||||
| REF 3 | Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands. Biochemistry. 2006 Jan 17;45(2):402-15. | |||||
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