Top ▲

peptidylprolyl cis/trans isomerase, NIMA-interacting 1

Click here for help

Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 3171

Nomenclature: peptidylprolyl cis/trans isomerase, NIMA-interacting 1

Family: Peptidyl-prolyl cis/trans isomerases

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 163 19p13 PIN1 peptidylprolyl cis/trans isomerase, NIMA-interacting 1
Mouse - 165 9 A3; 9 7.6 cM Pin1 peptidyl-prolyl cis/trans isomerase, NIMA-interacting 1
Rat - 165 8q13 Pin1 peptidylprolyl cis/trans isomerase, NIMA-interacting 1
Previous and Unofficial Names Click here for help
protein (peptidyl-prolyl cis/trans isomerase) NIMA-interacting 1 | peptidylprolyl cis/trans isomerase
Database Links Click here for help
Alphafold Q13526 (Hs), Q9QUR7 (Mm)
BRENDA 5.2.1.8
ChEMBL Target CHEMBL2288 (Hs)
Ensembl Gene ENSG00000127445 (Hs), ENSMUSG00000032171 (Mm), ENSRNOG00000020474 (Rn)
Entrez Gene 5300 (Hs), 23988 (Mm), 298696 (Rn)
Human Protein Atlas ENSG00000127445 (Hs)
KEGG Enzyme 5.2.1.8
KEGG Gene hsa:5300 (Hs), mmu:23988 (Mm), rno:298696 (Rn)
OMIM 601052 (Hs)
Pharos Q13526 (Hs)
RefSeq Nucleotide NM_006221 (Hs), NM_023371 (Mm), NM_001106701 (Rn)
RefSeq Protein NP_006212 (Hs), NP_075860 (Mm), NP_001100171 (Rn)
UniProtKB Q13526 (Hs), Q9QUR7 (Mm)
Wikipedia PIN1 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  PPIase in complex with a non-phosphate small molecule inhibitor
PDB Id:  4TYO
Ligand:  AG-17724
Resolution:  1.75Å
Species:  Human
References:  5
Enzyme Reaction Click here for help
EC Number: 5.2.1.8

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
AG-122018 Small molecule or natural product Hs Inhibition 7.9 pKi 5
⤷ pKi 7.9 (Ki 1.2x10-8 M) [5]
BJP-06-005-3 Peptide Hs Inhibition 7.8 pKi 13
⤷ pKi 7.8 (Ki 1.5x10-8 M) [13]
sulfopin Small molecule or natural product Hs Inhibition 6.7 – 7.8 pKi 3
⤷ pKi 7.8 (Ki 1.7x10-8 M) [3]
Description: Binding to Pin1 in a fluorescence polarization (FP) assay that measured competitive displacement of an N-terminal fluorescein-labeled peptide substrate (Bth-D-pThr-Pip-Nal)
pKi 6.7 (Ki 2.11x10-7 M) [3]
Description: Inhibition of Pin1 catalytic activity determined in a chymotrypsin-coupled peptidyl-prolyl isomerization assay (PPIase) assay
AG-17724 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.1 pKi 5
⤷ pKi 7.1 (Ki 8x10-8 M) [5]
Description: Inhibition of recombinant enzyme in vitro.
compound 20 [PMID: 25091930] Small molecule or natural product Hs Inhibition 6.7 pKi 5
⤷ pKi 6.7 (Ki 1.96x10-7 M) [5]
Immunopharmacology Comments
The role of PIN1 in modulating cytokine expression by activated T cells and eosinophils suggests that targeting this enzyme may offer potential for the development of therapeutics for immunologic diseases such as asthma and organ rejection [4,10-11,16].
Physiological Functions Click here for help
Converts P-tau from a cis conformation to a trans conformation. Cis P-tau has been detected in toxic tau tangles present in samples from patients with vascular dementia. Pin1 prevents neurodegeneration by limiting cis P-tau.
Species:  Human
Tissue: 
References:  7-9
Physiological Consequences of Altering Gene Expression Click here for help
Brain-specific Pin1 overexpression rescues vascular contributions to cognitive impairment and dementia (VCID)-like neurodegeneration and cognitive impairment in a mouse model; likely by reducing cis P-tau levels.
Species:  Mouse
Tissue:  Brain
Technique: 
References:  14
General Comments
PIN1 isomerises phosphorylated serine/threonine-proline bonds, a protein modification that is involved in the regulation of a range of cellular processes, including cell cycle progression [6] and protein folding and processing [1]. It has been proposed as a drug target for cancer [15] and diseases that are associated with defective amyloid protein processing such Alzheimer's disease [2,12]. Evidence also suggests that PIN1 plays a role in the immune system, in pathways that are distinct from those regulated by other immune system PPIases (peptidylprolyl isomerase A/cyclophilin A and FKBP prolyl isomerase 1A) [4].

References

Show »

1. Blair LJ, Baker JD, Sabbagh JJ, Dickey CA. (2015) The emerging role of peptidyl-prolyl isomerase chaperones in tau oligomerization, amyloid processing, and Alzheimer's disease. J Neurochem, 133 (1): 1-13. [PMID:25628064]

2. Butterfield DA, Abdul HM, Opii W, Newman SF, Joshi G, Ansari MA, Sultana R. (2006) Pin1 in Alzheimer's disease. J Neurochem, 98 (6): 1697-706. [PMID:16945100]

3. Dubiella C, Pinch BJ, Koikawa K, Zaidman D, Poon E, Manz TD, Nabet B, He S, Resnick E, Rogel A et al.. (2021) Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo. Nat Chem Biol, 17 (9): 954-963. [PMID:33972797]

4. Esnault S, Shen ZJ, Malter JS. (2008) Pinning down signaling in the immune system: the role of the peptidyl-prolyl isomerase Pin1 in immune cell function. Crit Rev Immunol, 28 (1): 45-60. [PMID:18298383]

5. Guo C, Hou X, Dong L, Marakovits J, Greasley S, Dagostino E, Ferre R, Johnson MC, Humphries PS, Li H et al.. (2014) Structure-based design of novel human Pin1 inhibitors (III): optimizing affinity beyond the phosphate recognition pocket. Bioorg Med Chem Lett, 24 (17): 4187-91. [PMID:25091930]

6. Göthel SF, Marahiel MA. (1999) Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts. Cell Mol Life Sci, 55 (3): 423-36. [PMID:10228556]

7. Liou YC, Sun A, Ryo A, Zhou XZ, Yu ZX, Huang HK, Uchida T, Bronson R, Bing G, Li X et al.. (2003) Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration. Nature, 424 (6948): 556-61. [PMID:12891359]

8. Lu KP, Zhou XZ. (2007) The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nat Rev Mol Cell Biol, 8 (11): 904-16. [PMID:17878917]

9. Lu PJ, Wulf G, Zhou XZ, Davies P, Lu KP. (1999) The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature, 399 (6738): 784-8. [PMID:10391244]

10. Nechama M, Kwon J, Wei S, Kyi AT, Welner RS, Ben-Dov IZ, Arredouani MS, Asara JM, Chen CH, Tsai CY et al.. (2018) The IL-33-PIN1-IRAK-M axis is critical for type 2 immunity in IL-33-induced allergic airway inflammation. Nat Commun, 9 (1): 1603. [PMID:29686383]

11. Oh J, Malter JS. (2013) Pin1-FADD interactions regulate Fas-mediated apoptosis in activated eosinophils. J Immunol, 190 (10): 4937-45. [PMID:23606538]

12. Pastorino L, Sun A, Lu PJ, Zhou XZ, Balastik M, Finn G, Wulf G, Lim J, Li SH, Li X et al.. (2006) The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature, 440 (7083): 528-34. [PMID:16554819]

13. Pinch BJ, Doctor ZM, Nabet B, Browne CM, Seo HS, Mohardt ML, Kozono S, Lian X, Manz TD, Chun Y et al.. (2020) Identification of a potent and selective covalent Pin1 inhibitor. Nat Chem Biol, 16 (9): 979-987. [PMID:32483379]

14. Qiu C, Albayram O, Kondo A, Wang B, Kim N, Arai K, Tsai CY, Bassal MA, Herbert MK, Washida K et al.. (2021) Cis P-tau underlies vascular contribution to cognitive impairment and dementia and can be effectively targeted by immunotherapy in mice. Sci Transl Med,. DOI: 10.1126/scitranslmed.aaz7615 [PMID:34078745]

15. Stifani S. (2018) The Multiple Roles of Peptidyl Prolyl Isomerases in Brain Cancer. Biomolecules, 8 (4): 112. [PMID:30314361]

16. Wei S, Yoshida N, Finn G, Kozono S, Nechama M, Kyttaris VC, Zhen Zhou X, Tsokos GC, Ping Lu K. (2016) Pin1-Targeted Therapy for Systemic Lupus Erythematosus. Arthritis Rheumatol, 68 (10): 2503-13. [PMID:27159270]

Contributors

Show »

How to cite this page