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proprotein convertase subtilisin/kexin type 9

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Target id: 2388

Nomenclature: proprotein convertase subtilisin/kexin type 9

Family: S8: Subtilisin

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 692 1p32.3 PCSK9 proprotein convertase subtilisin/kexin type 9
Mouse - 694 4 C7 Pcsk9 proprotein convertase subtilisin/kexin type 9
Rat - 691 5q34 Pcsk9 proprotein convertase subtilisin/kexin type 9
Previous and Unofficial Names Click here for help
FH3 | Narc1 | neural apoptosis-regulated convertase 1 | proprotein convertase 9 | proprotein convertase PC9
Database Links Click here for help
Specialist databases
MEROPS S08.039 (Hs)
Other databases
Alphafold Q8NBP7 (Hs), Q80W65 (Mm), P59996 (Rn)
BRENDA 3.4.21.-
CATH/Gene3D 3.30.70.80, 3.40.50.200
ChEMBL Target CHEMBL2929 (Hs)
Ensembl Gene ENSG00000169174 (Hs), ENSMUSG00000044254 (Mm), ENSRNOG00000006280 (Rn)
Entrez Gene 255738 (Hs), 100102 (Mm), 298296 (Rn)
Human Protein Atlas ENSG00000169174 (Hs)
KEGG Enzyme 3.4.21.-
KEGG Gene hsa:255738 (Hs), mmu:100102 (Mm), rno:298296 (Rn)
OMIM 607786 (Hs)
Pharos Q8NBP7 (Hs)
RefSeq Nucleotide NM_174936 (Hs), NM_153565 (Mm), NM_199253 (Rn)
RefSeq Protein NP_777596 (Hs), NP_705793 (Mm), NP_954862 (Rn)
UniProtKB Q8NBP7 (Hs), Q80W65 (Mm), P59996 (Rn)
Wikipedia PCSK9 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  PCSK9 in complex with compound 16
PDB Id:  6U26
Ligand:  compound 16 [PMID: 31653597]
Resolution:  1.53Å
Species:  Human
References:  12
Enzyme Reaction Click here for help
EC Number: 3.4.21.-

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
MK-0616 Small molecule or natural product Hs Binding 11.3 pKi 7
⤷ pKi 11.3 (Ki 5x10-12 M) [7]
Description: Binding affinity for hPCSK9 determined in a TR-FRET assay
SBC-115,337 Small molecule or natural product Hs Inhibition 6.2 – 6.3 pIC50 1
⤷ pIC50 6.2 – 6.3 (IC50 6x10-7 – 5x10-7 M) [1]
Description: Inhibition of the PCSK9/ LDLR interaction in an ELISA
Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
bococizumab Peptide Primary target of this compound Hs Binding 10.0 pKd 8
⤷ pKd 10.0 (Kd 1x10-10 M) [8]
Description: Affinity for hPCSK9 measured using proprietary BIACore® technology.
evolocumab Peptide Approved drug Primary target of this compound Hs Binding 9.7 pKd 6
⤷ pKd 9.7 (Kd 1.9x10-10 M) [6]
Description: Dissociation equilibrium constant for wild-type hPCSK9, measured using proprietary BIACore® technology.
alirocumab Peptide Approved drug Primary target of this compound Hs Binding 9.4 pKd 17
⤷ pKd 9.4 (Kd 3.77x10-10 M) [17]
tafolecimab Peptide Approved drug Hs Binding - - 19
⤷ [19]
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 16 [PMID: 31653597] Small molecule or natural product Ligand has a PDB structure Hs Binding 7.0 pKi 12
⤷ pKi 7.0 (Ki 1.07x10-7 M) [12]
Description: Determined in a fluorescence polarization assay.
Immuno Process Associations
Immuno Process:  Antigen presentation
Physiological Functions Click here for help
PCSK9 may be an inflammatory mediator in the pathogenesis of atherosclerosis.
Species:  Mouse
Tissue:  Atherosclerotic vascular lesions and macrophages.
References:  18
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Hypercholesterolemia; autosomal dominant, 3
Synonyms: Familial hypercholesterolemia [Disease Ontology: DOID:13810]
Disease Ontology: DOID:13810
OMIM: 603776
References:  3,5
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human S127R 625T>A 2
Missense Human F216L 890T>C 2
Missense Human D374Y Patients carrying this gain of function mutation exhibit lower plasma concentrations of PCSK9 5
Biologically Significant Variants Click here for help
Type:  Naturally occurring SNP
Species:  Human
Description:  Nucleotide change 625T->A causes a Ser to Arg substitution
Amino acid change:  S127R
Amino acids:  692
SNP accession:  rs28942111
Validation:  1000 Genomes, HapMap, Cited, Frequency, Multiple observations
References:  3
Type:  Naturally occurring SNPs
Species:  Human
Description:  Nucleotide change 890T->C causes a Phe to Leu substitution
Amino acid change:  F216L
Amino acids:  692
SNP accession:  rs28942112
Validation:  1000 Genomes, HapMap, Cited, Frequency, Multiple observations
References:  3
Biologically Significant Variant Comments
Healthy individuals carrying the PCSK9 R46L variant exhibit lower plasma concentrations of PCSK9 [5].
General Comments
Mature PCSK9 protein is secreted from hepatocytes. The enzyme acts to reduce the levels of LDL receptors by binding to local LDL receptor-cholesterol complexes, inducing their endocytic internalisation and degradation [4,9,13-15,20]. This function of PCSK9 helps to modulate LDL metabolism. Inhibition of PCSK9 results in increased numbers of LDL receptors on hepatocyte membranes [10] which promotes LDL clearance. PCSK9 is being actively pursued as a mechanistic target for the development of novel agents to treat hypercholesterolemia, especially for patients who do not respond to or don't tolerate statin treatment. The focus to date has been on the development of anti-PCSK9 monoclonal antibodies, and two such therapeutics have already reached the clinic, namely evolocumab and alirocumab [11]. Development of alternatives to the antibody-based PCSK9-inhibition strategy are the focus of multiple research projects [16]. In late 2020, the EMA approved Novartis' inclisiran (Leqvio®; ALN-60212) which is a first-in-class siRNA-based drug that reduces expression of PCSK9 and thereby lowers low-density lipoprotein cholesterol (LDL-C). Leqvio® is indicated as a long-acting (administered twice yearly) treatment for hypercholesterolemia or mixed dyslipidemia. FDA approval of Leqvio® followed in December 2021.

References

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1. Abdel-Meguid SS, Elshourbagy NA, Meyers HV, Mousa SA. (2017) Anti-proprotein convertase subtilisin kexin type 9 (anti-pcsk9) compounds and methods of using the same in the treatment and/or prevention of cardiovascular diseases. Patent number: WO2017222953A1. Assignee: Shifa Biomedical Corporation. Priority date: 21/06/2016. Publication date: 28/12/2017.

2. Abifadel M, Elbitar S, El Khoury P, Ghaleb Y, Chémaly M, Moussalli ML, Rabès JP, Varret M, Boileau C. (2014) Living the PCSK9 Adventure: from the Identification of a New Gene in Familial Hypercholesterolemia Towards a Potential New Class of Anticholesterol Drugs. Curr Atheroscler Rep, 16 (9): 439. [PMID:25052769]

3. Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D et al.. (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet, 34 (2): 154-6. [PMID:12730697]

4. DeVay RM, Shelton DL, Liang H. (2013) Characterization of proprotein convertase subtilisin/kexin type 9 (PCSK9) trafficking reveals a novel lysosomal targeting mechanism via amyloid precursor-like protein 2 (APLP2). J Biol Chem, 288 (15): 10805-18. [PMID:23430252]

5. Humphries SE, Neely RD, Whittall RA, Troutt JS, Konrad RJ, Scartezini M, Li KW, Cooper JA, Acharya J, Neil A. (2009) Healthy individuals carrying the PCSK9 p.R46L variant and familial hypercholesterolemia patients carrying PCSK9 p.D374Y exhibit lower plasma concentrations of PCSK9. Clin Chem, 55 (12): 2153-61. [PMID:19797716]

6. Jackson SM, Shan B, Shen W, King CT. Antigen binding proteins to proprotein convertase subtilisin kexin type 9 (PCSK9). Patent number: US8030457. Assignee: Amgen, Inc.. Priority date: 23/08/2007. Publication date: 04/10/2011.

7. Johns DG, Campeau LC, Banka P, Bautmans A, Bueters T, Bianchi E, Branca D, Bulger PG, Crevecoeur I, Ding FX et al.. (2023) Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor. Circulation, 148 (2): 144-158. [PMID:37125593]

8. Liang H et al. Isolated antibody which specifically binds to PCSK9. Patent number: US8080243. Assignee: Rinat Neuroscience Corp., Pfizer Inc.. Priority date: 12/09/2008. Publication date: 20/12/2011.

9. Mbikay M, Mayne J, Chrétien M. (2013) Proprotein convertases subtilisin/kexin type 9, an enzyme turned escort protein: hepatic and extra hepatic functions. J Diabetes, 5 (4): 391-405. [PMID:23714205]

10. McNutt MC, Kwon HJ, Chen C, Chen JR, Horton JD, Lagace TA. (2009) Antagonism of secreted PCSK9 increases low density lipoprotein receptor expression in HepG2 cells. J Biol Chem, 284 (16): 10561-70. [PMID:19224862]

11. Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, Brockmeyer M, Kandzari DE, Kubica JM, D'Agostino Sr RB et al.. (2015) Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis. Ann Intern Med, 163 (1): 40-51. [PMID:25915661]

12. Petrilli WL, Adam GC, Erdmann RS, Abeywickrema P, Agnani V, Ai X, Baysarowich J, Byrne N, Caldwell JP, Chang W et al.. (2020) From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9. Cell Chem Biol, 27 (1): 32-40.e3. [PMID:31653597]

13. Qian YW, Schmidt RJ, Zhang Y, Chu S, Lin A, Wang H, Wang X, Beyer TP, Bensch WR, Li W et al.. (2007) Secreted PCSK9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis. J Lipid Res, 48 (7): 1488-98. [PMID:17449864]

14. Seidah NG, Abifadel M, Prost S, Boileau C, Prat A. (2017) The Proprotein Convertases in Hypercholesterolemia and Cardiovascular Diseases: Emphasis on Proprotein Convertase Subtilisin/Kexin 9. Pharmacol Rev, 69 (1): 33-52. [PMID:27920219]

15. Seidah NG, Awan Z, Chrétien M, Mbikay M. (2014) PCSK9: a key modulator of cardiovascular health. Circ Res, 114 (6): 1022-36. [PMID:24625727]

16. Seidah NG, Prat A, Pirillo A, Catapano AL, Norata GD. (2019) Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies. Cardiovasc Res, 115 (3): 510-518. [PMID:30629143]

17. Sleeman MW, Martin JH, Huang TT, MacDonald D. (2011) High affinity human antibodies to PCSK9. Patent number: US8062640. Assignee: Regeneron Pharmaceuticals, Inc.. Priority date: 15/12/2008. Publication date: 22/11/2011.

18. Tang ZH, Peng J, Ren Z, Yang J, Li TT, Li TH, Wang Z, Wei DH, Liu LS, Zheng XL et al.. (2017) New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4/NF-κB pathway. Atherosclerosis, 262: 113-122. [PMID:28535426]

19. Tsun A, Krauland E, Belk JP, Maio X, Zhang M, Boland N, Liu X, Yo D. (2022) Anti-PCSK9 antibody and use thereof. Patent number: US11485795B2. Assignee: Innovent Biologics Suzhou Co Ltd. Priority date: 03/04/2023. Publication date: 22/12/2017.

20. Wang Y, Huang Y, Hobbs HH, Cohen JC. (2012) Molecular characterization of proprotein convertase subtilisin/kexin type 9-mediated degradation of the LDLR. J Lipid Res, 53 (9): 1932-43. [PMID:22764087]

How to cite this page

S8: Subtilisin: proprotein convertase subtilisin/kexin type 9. Last modified on 19/05/2023. Accessed on 20/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2388.