Target Information
| Target General Information | Top | |||||
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| Target ID |
T99029
(Former ID: TTDNR00633)
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| Target Name |
Pyruvate dehydrogenase kinase 3 (PDHK3)
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| Synonyms |
Pyruvate dehydrogenase kinase isoform 3; PDK3
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| Gene Name |
PDK3
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
Inhibits pyruvatedehydrogenase activity by phosphorylation of the E1 subunit PDHA1, and thereby regulates glucose metabolism and aerobic respiration. Can also phosphorylate PDHA2. Decreases glucose utilization and increases fat metabolism in response to prolonged fasting, and as adaptation to a high-fat diet. Plays a role in glucose homeostasis and in maintaining normal blood glucose levels in function of nutrient levels and under starvation. Plays a role in the generation of reactive oxygen species.
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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 |
MRLFRWLLKQPVPKQIERYSRFSPSPLSIKQFLDFGRDNACEKTSYMFLRKELPVRLANT
MREVNLLPDNLLNRPSVGLVQSWYMQSFLELLEYENKSPEDPQVLDNFLQVLIKVRNRHN DVVPTMAQGVIEYKEKFGFDPFISTNIQYFLDRFYTNRISFRMLINQHTLLFGGDTNPVH PKHIGSIDPTCNVADVVKDAYETAKMLCEQYYLVAPELEVEEFNAKAPDKPIQVVYVPSH LFHMLFELFKNSMRATVELYEDRKEGYPAVKTLVTLGKEDLSIKISDLGGGVPLRKIDRL FNYMYSTAPRPSLEPTRAAPLAGFGYGLPISRLYARYFQGDLKLYSMEGVGTDAVIYLKA LSSESFERLPVFNKSAWRHYKTTPEADDWSNPSSEPRDASKYKAKQ Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| 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 structure of the PDK3-L2 complex | PDB:1Y8P | ||||
| Method | X-ray diffraction | Resolution | 2.63 Å | Mutation | No | [2] |
| PDB Sequence |
VPKQIERYSR
21 FSPSPLSIKQ31 FLDFGRDNAC41 EKTSYMFLRK51 ELPVRLANTM61 REVNLLPDNL 71 LNRPSVGLVQ81 SWYMQSFLEL91 LEYENKSPED101 PQVLDNFLQV111 LIKVRNRHND 121 VVPTMAQGVI131 EYKEKFGFDP141 FISTNIQYFL151 DRFYTNRISF161 RMLINQHTLL 171 FGGDTNPVHP181 KHIGSIDPTC191 NVADVVKDAY201 ETAKMLCEQY211 YLVAPELEVE 221 EFNAKAPDKP231 IQVVYVPSHL241 FHMLFELFKN251 SMRATVELYE261 DRKEGYPAVK 271 TLVTLGKEDL281 SIKISDLGGG291 VPLRKIDRLF301 NYMYSTAPRP320 LAGFGYGLPI 330 SRLYARYFQG340 DLKLYSMEGV350 GTDAVIYLKA360 LSSESFERLP370 VFNKSAWRHY 380 KTTPEADDWS390 NPSSEPRDAS400 K
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GLU247
3.273
LYS250
3.398
ASN251
2.697
SER252
3.955
ARG254
3.328
ALA255
3.514
ASP287
2.857
GLY289
4.992
GLY291
4.290
VAL292
3.417
LEU300
3.653
TYR305
3.309
SER306
2.737
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| Ligand Name: adenosine diphosphate | Ligand Info | |||||
| Structure Description | Crystal structure of the PDK3-L2 complex | PDB:1Y8O | ||||
| Method | X-ray diffraction | Resolution | 2.48 Å | Mutation | No | [2] |
| PDB Sequence |
PKQIERYSRF
22 SPSPLSIKQF32 LDFGRDNACE42 KTSYMFLRKE52 LPVRLANTMR62 EVNLLPDNLL 72 NRPSVGLVQS82 WYMQSFLELL92 EYENKSPEDP102 QVLDNFLQVL112 IKVRNRHNDV 122 VPTMAQGVIE132 YKEKFGFDPF142 ISTNIQYFLD152 RFYTNRISFR162 MLINQHTLLF 172 GGDTNPVHPK182 HIGSIDPTCN192 VADVVKDAYE202 TAKMLCEQYY212 LVAPELEVEE 222 FNAKAPDKPI232 QVVYVPSHLF242 HMLFELFKNS252 MRATVELYED262 RKEGYPAVKT 272 LVTLGKEDLS282 IKISDLGGGV292 PLRKIDRLFN302 YMYSPLFGYG327 LPISRLYARY 337 FQGDLKLYSM347 EGVGTDAVIY357 LKALSSESFE367 RLPVFNKSAW377 RHYKTTPEAD 387 DWSNPSSEPR397 DASK
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GLU247
4.505
ASN251
3.189
SER252
3.708
ARG254
2.703
ALA255
3.520
ASP287
2.821
GLY289
4.890
GLY291
4.409
VAL292
3.337
LEU300
3.070
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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 | 0.00E+00 |
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| Closeness centrality | 1.71E-01 | Radiality | 1.27E+01 | Clustering coefficient | 1.00E+00 |
| Neighborhood connectivity | 1.90E+01 | Topological coefficient | 4.75E-01 | Eccentricity | 13 |
| 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 | ||||||
| References | Top | |||||
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| REF 1 | Inactivation of the HIF-1/PDK3 signaling axis drives melanoma toward mitochondrial oxidative metabolism and potentiates the therapeutic activity o... Cancer Res. 2012 Oct 1;72(19):5035-47. | |||||
| REF 2 | Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of human pyruvate dehydrogenase complex. EMBO J. 2005 May 18;24(10):1763-74. | |||||
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