Top ▲

PAS domain containing serine/threonine kinase

Click here for help

Target id: 2139

Nomenclature: PAS domain containing serine/threonine kinase

Abbreviated Name: PASK

Family: PASK subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1323 2q37.3 PASK PAS domain containing serine/threonine kinase
Mouse - 1383 1 D Pask PAS domain containing serine/threonine kinase
Rat - 1385 9 q36 Pask PAS domain containing serine/threonine kinase
Previous and Unofficial Names Click here for help
PASKIN | Per-Arnt-Sim (PAS) kinase | STK37
Database Links Click here for help
Alphafold Q96RG2 (Hs), Q8CEE6 (Mm)
BRENDA 2.7.11.1
ChEMBL Target CHEMBL6054 (Hs)
Ensembl Gene ENSG00000115687 (Hs), ENSMUSG00000026274 (Mm), ENSRNOG00000016888 (Rn)
Entrez Gene 23178 (Hs), 269224 (Mm), 301617 (Rn)
Human Protein Atlas ENSG00000115687 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:23178 (Hs), mmu:269224 (Mm), rno:301617 (Rn)
OMIM 607505 (Hs)
Pharos Q96RG2 (Hs)
RefSeq Nucleotide NM_015148 (Hs), NM_080850 (Mm), NM_001009362 (Rn)
RefSeq Protein NP_055963 (Hs), NP_543126 (Mm), NP_001009362 (Rn)
UniProtKB Q96RG2 (Hs), Q8CEE6 (Mm)
Wikipedia PASK (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human PAS kinase bound to ADP
PDB Id:  3DLS
Ligand:  ADP   This ligand is endogenous
Resolution:  2.3Å
Species:  Human
References:  8
Image of receptor 3D structure from RCSB PDB
Description:  Structure and interactions of PAS kinase N-terminal PAS domain: Model for intramolecular kinase regulation
PDB Id:  1LL8
Resolution:  0.0Å
Species:  Human
References:  1
Enzyme Reaction Click here for help
EC Number: 2.7.11.1

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
PP-242 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition - - 3
⤷ [3]
Description: Measured as % inhibition at 1μM compound.
Inhibitor Comments
Compound PP-242 inhibits PASK activity by approximately 74% at 1μM [3].
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: 2,5
Key to terms and symbols Click column headers to sort
Target used in screen: PASK/PASK
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 3.7 4.5 -1.5
K-252a Small molecule or natural product Hs Inhibitor Inhibition 14.6 14.0 4.0
casein kinase II inhibitor III Small molecule or natural product Hs Inhibitor Inhibition 24.8 63.0 6.0
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 32.0 40.0 -1.0
isogranulatimide Small molecule or natural product Hs Inhibitor Inhibition 33.6 57.0 26.0
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 40.9 46.0 2.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 43.3 117.0 104.0
JAK3 inhibitor II Small molecule or natural product Hs Inhibitor Inhibition 57.9 73.0 8.0
JNK inhibitor V Small molecule or natural product Hs Inhibitor Inhibition 64.1 90.0 36.0
GF109203X Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 67.0 74.0 18.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Physiological Consequences of Altering Gene Expression Click here for help
PASK knockout prevents the development of obesity and non-alcoholic fatty liver in mice fed with a high-fat diet. PASK-/- mice are almost completely protected from the obesity and insulin resistance which would be expected to develop in response to a high-fat diet.
Species:  Mouse
Tissue: 
Technique: 
References:  6
General Comments
PAS domain containing serine/threonine kinase (PASK) acts as a nutrient and energy sensor in multiple tissues [7]. Experimental evidence suggests that PASK may be a druggable target for the development of novel therapeutics for metabolic disease [7,9]. Galapagos claimed PASK inhibiting compounds in patent WO2020173739, for the treatment of type 2 diabetes [4]. We can speculate that their lead GLPG4059 (Phase1 NCT04575818) was one of these PASK inhibitors. However, no name-to-structure has been formally disclosed, and GLPG4059 was cut from Galapagos' pipeline in the first half 2021.

References

Show »

1. Amezcua CA, Harper SM, Rutter J, Gardner KH. (2002) Structure and interactions of PAS kinase N-terminal PAS domain: model for intramolecular kinase regulation. Structure, 10 (10): 1349-61. [PMID:12377121]

2. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

3. Apsel B, Blair JA, Gonzalez B, Nazif TM, Feldman ME, Aizenstein B, Hoffman R, Williams RL, Shokat KM, Knight ZA. (2008) Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem Biol, 4 (11): 691-9. [PMID:18849971]

4. Beaumont SNA, Bock XM, Comas Martinez D, Joncour AM, Labeguere FG, Lopez Ramos M, Temal-Laib T. (2020) PYRAZOLOPYRIDINE DERIVATIVES AS INHIBITORS OF PASK. Patent number: WO2020173739. Assignee: GALAPAGOS NV. Priority date: 25/02/2019. Publication date: 03/09/2020.

5. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J, 451 (2): 313-28. [PMID:23398362]

6. Hao HX, Cardon CM, Swiatek W, Cooksey RC, Smith TL, Wilde J, Boudina S, Abel ED, McClain DA, Rutter J. (2007) PAS kinase is required for normal cellular energy balance. Proc Natl Acad Sci U S A, 104 (39): 15466-71. [PMID:17878307]

7. Hurtado-Carneiro V, Pérez-García A, Alvarez E, Sanz C. (2020) PAS Kinase: A Nutrient and Energy Sensor "Master Key" in the Response to Fasting/Feeding Conditions. Front Endocrinol (Lausanne), 11: 594053. [PMID:33391184]

8. Kikani CK, Antonysamy SA, Bonanno JB, Romero R, Zhang FF, Russell M, Gheyi T, Iizuka M, Emtage S, Sauder JM et al.. (2010) Structural bases of PAS domain-regulated kinase (PASK) activation in the absence of activation loop phosphorylation. J Biol Chem, 285 (52): 41034-43. [PMID:20943661]

9. Pape JA, Newey CR, Burrell HR, Workman A, Perry K, Bikman BT, Bridgewater LC, Grose JH. (2018) Per-Arnt-Sim Kinase (PASK) Deficiency Increases Cellular Respiration on a Standard Diet and Decreases Liver Triglyceride Accumulation on a Western High-Fat High-Sugar Diet. Nutrients, 10 (12). DOI: 10.3390/nu10121990 [PMID:30558306]

How to cite this page

PASK subfamily: PAS domain containing serine/threonine kinase. Last modified on 10/05/2021. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2139.