Target Information
| Target General Information | Top | |||||
|---|---|---|---|---|---|---|
| Target ID |
T08813
(Former ID: TTDR00977)
|
|||||
| Target Name |
cAMP-dependent protein kinase A type I (PRKAR1A)
|
|||||
| Synonyms |
cAMP-dependent protein kinase type I-alpha regulatory subunit; Tissue-specific extinguisher 1; TSE1; PRKAR1; PKR1
Click to Show/Hide
|
|||||
| Gene Name |
PRKAR1A
|
|||||
| Target Type |
Literature-reported target
|
[1] | ||||
| Function |
Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells.
Click to Show/Hide
|
|||||
| BioChemical Class |
Kinase
|
|||||
| UniProt ID | ||||||
| Sequence |
MESGSTAASEEARSLRECELYVQKHNIQALLKDSIVQLCTARPERPMAFLREYFERLEKE
EAKQIQNLQKAGTRTDSREDEISPPPPNPVVKGRRRRGAISAEVYTEEDAASYVRKVIPK DYKTMAALAKAIEKNVLFSHLDDNERSDIFDAMFSVSFIAGETVIQQGDEGDNFYVIDQG ETDVYVNNEWATSVGEGGSFGELALIYGTPRAATVKAKTNVKLWGIDRDSYRRILMGSTL RKRKMYEEFLSKVSILESLDKWERLTVADALEPVQFEDGQKIVVQGEPGDEFFIILEGSA AVLQRRSENEEFVEVGRLGPSDYFGEIALLMNRPRAATVVARGPLKCVKLDRPRFERVLG PCSDILKRNIQQYNSFVSLSV Click to Show/Hide
|
|||||
| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T50HKY | |||||
| Cell-based Target Expression Variations | Top | |||||
|---|---|---|---|---|---|---|
| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| Ligand Name: Cyclic Guanosine Monophosphate | Ligand Info | |||||
| Structure Description | Co-crystal structure of PKA RI alpha CNB-B mutant (G316R/A336T) with cGMP | PDB:5KJZ | ||||
| Method | X-ray diffraction | Resolution | 1.35 Å | Mutation | Yes | [5] |
| PDB Sequence |
SILMGSTLRK
242 RKMYEEFLSK252 VSILESLDKW262 ERLTVADALE272 PVQFEDGQKI282 VVQGEPGDEF 292 FIILEGSAAV302 LQRRSENEEF312 VEVRRLGPSD322 YFGEIALLMN332 RPRTATVVAR 342 GPLKCVKLDR352 PRFERVLGPC362 SDILKRNIQQ372 YNSFVSLSV
|
|||||
|
|
VAL283
3.933
VAL302
3.758
GLN304
3.439
VAL315
3.552
ARG316
2.895
LEU318
4.765
TYR323
4.485
PHE324
3.198
GLY325
2.869
GLU326
2.593
|
|||||
| Ligand Name: [3H]cAMP | Ligand Info | |||||
| Structure Description | Co-crystal Structure of PKA RI alpha CNB-B domain with cAMP | PDB:5KJX | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [5] |
| PDB Sequence |
RKRKMYEEFL
250 SKVSILESLD260 KWERLTVADA270 LEPVQFEDGQ280 KIVVQGEPGD290 EFFIILEGSA 300 AVLQRRSENE310 EFVEVGRLGP320 SDYFGEIALL330 MNRPRAATVV340 ARGPLKCVKL 350 DRPRFERVLG360 PCSDILKRNI370 QQYNSFVSLS380 V
|
|||||
|
|
VAL283
3.849
VAL302
3.701
GLN304
3.618
VAL315
4.235
LEU318
4.914
TYR323
4.479
PHE324
3.215
GLY325
2.974
GLU326
2.574
ILE327
3.216
|
|||||
| 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 |
|---|---|
|
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
|
|
|
There is no similarity protein (E value < 0.005) for this target
|
|
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.
|
| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
|---|---|---|---|
| Insulin signaling pathway | hsa04910 | Affiliated Target |
|
| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 10 | Degree centrality | 1.07E-03 | Betweenness centrality | 3.66E-04 |
|---|---|---|---|---|---|
| Closeness centrality | 2.12E-01 | Radiality | 1.37E+01 | Clustering coefficient | 4.00E-01 |
| Neighborhood connectivity | 1.56E+01 | Topological coefficient | 1.49E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Drug Property Profile of Target | Top | |
|---|---|---|
| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
|
|
||
| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
|
|
||
| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
|
|
||
| "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 Regulators | Top | |||||
|---|---|---|---|---|---|---|
| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target-Related Models and Studies | Top | |||||
|---|---|---|---|---|---|---|
| Target Validation | ||||||
| References | Top | |||||
|---|---|---|---|---|---|---|
| REF 1 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 2 | Liquid-phase synthesis of a pegylated adenosine-oligoarginine conjugate, cell-permeable inhibitor of cAMP-dependent protein kinase. Bioorg Med Chem Lett. 2003 Sep 15;13(18):3035-9. | |||||
| REF 3 | Adenosine-5'-carboxylic acid peptidyl derivatives as inhibitors of protein kinases. Bioorg Med Chem Lett. 1999 May 17;9(10):1447-52. | |||||
| REF 4 | Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. J Med Chem. 1992 Jan;35(1):177-84. | |||||
| REF 5 | Mutations of PKA cyclic nucleotide-binding domains reveal novel aspects of cyclic nucleotide selectivity. Biochem J. 2017 Jul 6;474(14):2389-2403. | |||||
If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.