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peptidylprolyl isomerase A

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2751

Nomenclature: peptidylprolyl isomerase A

Abbreviated Name: Cyclophilin A

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 - 165 7p13 PPIA peptidylprolyl isomerase A
Mouse - 164 11 3.97 cM Ppia peptidylprolyl isomerase A
Rat - 164 14q21 Ppia peptidylprolyl isomerase A
Previous and Unofficial Names Click here for help
CYPA | peptidylprolyl isomerase A (cyclophilin A)
Database Links Click here for help
Alphafold P62937 (Hs), P17742 (Mm), P10111 (Rn)
BRENDA 5.2.1.8
CATH/Gene3D 2.40.100.10
ChEMBL Target CHEMBL1949 (Hs), CHEMBL2780 (Rn)
Ensembl Gene ENSG00000196262 (Hs), ENSMUSG00000071866 (Mm), ENSRNOG00000027864 (Rn), ENSRNOG00000068764 (Rn)
Entrez Gene 5478 (Hs), 268373 (Mm), 25518 (Rn)
Human Protein Atlas ENSG00000196262 (Hs)
KEGG Enzyme 5.2.1.8
KEGG Gene hsa:5478 (Hs), mmu:268373 (Mm), rno:25518 (Rn)
OMIM 123840 (Hs)
Pharos P62937 (Hs)
RefSeq Nucleotide NM_021130 (Hs), NM_008907 (Mm), NM_017101 (Rn)
RefSeq Protein NP_066953 (Hs), NP_032933 (Mm), NP_058797 (Rn)
SynPHARM 79182 (in complex with cyclosporin A)
UniProtKB P62937 (Hs), P17742 (Mm), P10111 (Rn)
Wikipedia PPIA (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Complex of human peptidyl-prolyl cis-trans isomerase A (PPIA, cyclophilin A) and cyclosporin A
PDB Id:  2X2C
Ligand:  cyclosporin A
Resolution:  2.41Å
Species:  Human
References:  7
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of cyclophilin A in complex with Voclosporin E-ISA247
PDB Id:  3odi
Ligand:  voclosporin
Resolution:  2.2Å
Species:  Human
References:  5
Image of receptor 3D structure from RCSB PDB
Description:  Structure of human cyclophilin A in complex with the novel immunosuppressant sanglifehrin A at 1.6A resolution
PDB Id:  1YND
Ligand:  Sanglifehrin A
Resolution:  1.6Å
Species:  Human
References: 
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
Sanglifehrin A Small molecule or natural product Ligand has a PDB structure Hs Inhibition 8.5 pKd 9
⤷ pKd 8.5 (Kd 3.3x10-9 M) [9]
voclosporin Peptide Approved drug Primary target of this compound Immunopharmacology Ligand Hs Binding 7.8 pKd 5
⤷ pKd 7.8 (Kd 1.5x10-8 M) [5]
CRV431 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.9 pKi 6
⤷ pKi 8.9 (Ki 1.3x10-9 M) [6]
Description: Competitive enzyme inhibition measured in a cyclophilin A isomerase-based assay using recombinant enzyme
cyclosporin A Peptide Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.8 pKi 6
⤷ pKi 7.8 (Ki 1.72x10-8 M) [6]
Sanglifehrin A Small molecule or natural product Ligand has a PDB structure Hs Inhibition 9.0 pIC50 1
⤷ pIC50 9.0 (IC50 1x10-9 M) [1]
Description: Competitive inhibition of cylosporin A binding in a cell-free assay
CRV431 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.6 pIC50 6
⤷ pIC50 8.6 (IC50 2.5x10-9 M) [6]
cyclosporin A Peptide Approved drug Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.3 pIC50 2
⤷ pIC50 8.3 (IC50 5x10-9 M) Inhibition of the phosphatase activity of calcineurin in Jurkat cells. [2]
Inhibitor Comments
Cyclosporin A does not inhibit calcineurin activity directly. It must be in complex with its immunophilin 'receptor', cyclophilin A (PPIA), before it is able to bind and inhibit calcineurin [8].
Immunopharmacology Comments
Cyclophilin A (CypA) is well known as a specific binding protein for cyclosporin A (CsA) [3]. It is this mechanism that inhibits the calcineurin pathway, an effect that has long been used for immunosuppression in humans [10]. In addition CypA is a molecular chaperone that modulates protein folding by catalyzing cis‐trans isomerization at proline residues (peptidyl‐prolyl cis‐trans isomerase, or PPIase, activity). CypA has intracellular activities, and extracellular functions when it is secreted, either in response to inflammatory activation or as a response to oxidative stress [11]. Extracellular CypA has been proposed as an endogenous ligand for the innate immune triggering receptor expressed on myeloid cells 2 (TREM2: TREM2; Q9NZC2) [4]. In this role CypA influences TREM2 signaling.
Immuno Process Associations
Immuno Process:  Barrier integrity
Immuno Process:  Inflammation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling

References

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1. Bänteli R, Wagner J, Zenke G. (2001) Synthesis of derivatives of the novel cyclophilin-binding immunosuppressant sanglifehrin A with reduced numbers of polar functions. Bioorg Med Chem Lett, 11 (12): 1609-12. [PMID:11412991]

2. Fruman DA, Klee CB, Bierer BE, Burakoff SJ. (1992) Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A. Proc Natl Acad Sci USA, 89 (9): 3686-90. [PMID:1373887]

3. Handschumacher RE, Harding MW, Rice J, Drugge RJ, Speicher DW. (1984) Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science, 226 (4674): 544-7. [PMID:6238408]

4. Ji KY, Kim SM, Yee SM, Kim MJ, Ban YJ, Kim EM, Lee EH, Choi HR, Yun H, Lee CW et al.. (2021) Cyclophilin A is an endogenous ligand for the triggering receptor expressed on myeloid cells-2 (TREM2). FASEB J, 35 (4): e21479. [PMID:33710680]

5. Kuglstatter A, Mueller F, Kusznir E, Gsell B, Stihle M, Thoma R, Benz J, Aspeslet L, Freitag D, Hennig M. (2011) Structural basis for the cyclophilin A binding affinity and immunosuppressive potency of E-ISA247 (voclosporin). Acta Crystallogr D Biol Crystallogr, 67 (Pt 2): 119-23. [PMID:21245533]

6. Kuo J, Bobardt M, Chatterji U, Mayo PR, Trepanier DJ, Foster RT, Gallay P, Ure DR. (2019) A Pan-Cyclophilin Inhibitor, CRV431, Decreases Fibrosis and Tumor Development in Chronic Liver Disease Models. J Pharmacol Exp Ther, 371 (2): 231-241. [PMID:31406003]

7. Lammers M, Neumann H, Chin JW, James LC. (2010) Acetylation regulates cyclophilin A catalysis, immunosuppression and HIV isomerization. Nat Chem Biol, 6 (5): 331-7. [PMID:20364129]

8. Liu J, Farmer Jr JD, Lane WS, Friedman J, Weissman I, Schreiber SL. (1991) Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell, 66 (4): 807-15. [PMID:1715244]

9. Mackman RL, Steadman VA, Dean DK, Jansa P, Poullennec KG, Appleby T, Austin C, Blakemore CA, Cai R, Cannizzaro C et al.. (2018) Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle. J Med Chem, 61 (21): 9473-9499. [PMID:30074795]

10. Porter Jr GA, Beutner G. (2018) Cyclophilin D, Somehow a Master Regulator of Mitochondrial Function. Biomolecules, 8 (4). [PMID:30558250]

11. Yurchenko V, Constant S, Eisenmesser E, Bukrinsky M. (2010) Cyclophilin-CD147 interactions: a new target for anti-inflammatory therapeutics. Clin Exp Immunol, 160 (3): 305-17. [PMID:20345978]

Contributors

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