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proprotein convertase subtilisin/kexin type 9

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Target not currently curated in GtoImmuPdb

Target id: 2388

Nomenclature: proprotein convertase subtilisin/kexin type 9

Family: S8: Subtilisin

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
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
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:  10
Enzyme Reaction Click here for help
EC Number: 3.4.21.-

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Inhibitors
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
bococizumab Peptide Primary target of this compound Hs Inhibition 10.0 pKd 6
pKd 10.0 (Kd 1x10-10 M) [6]
Description: Affinity for hPCSK9 measured using proprietary BIACore® technology.
evolocumab Peptide Approved drug Primary target of this compound Hs Inhibition 9.7 pKd 5
pKd 9.7 (Kd 1.9x10-10 M) [5]
Description: Dissociation equilibrium constant for wild-type hPCSK9, measured using proprietary BIACore® technology.
alirocumab Peptide Approved drug Primary target of this compound Hs Inhibition 9.4 pKd 15
pKd 9.4 (Kd 3.77x10-10 M) [15]
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 10
pKi 7.0 (Ki 1.07x10-7 M) [10]
Description: Determined in a fluorescence polarization assay.
Immuno Process Associations
Immuno Process:  Antigen presentation
GO Annotations:  Associated to 4 GO processes
GO:0002092 positive regulation of receptor internalization IDA
GO:0034383 low-density lipoprotein particle clearance TAS
GO:1905598 negative regulation of low-density lipoprotein receptor activity IDA
GO:1905601 negative regulation of receptor-mediated endocytosis involved in cholesterol transport IDA
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:  16
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:  2,4
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human S127R 625T>A 1
Missense Human F216L 890T>C 1
Missense Human D374Y Patients carrying this gain of function mutation exhibit lower plasma concentrations of PCSK9 4
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: 
Validation:  1000 Genomes, HapMap, Cited, Frequency, Multiple observations
References:  2
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: 
Validation:  1000 Genomes, HapMap, Cited, Frequency, Multiple observations
References:  2
Biologically Significant Variant Comments
Healthy individuals carrying the PCSK9 R46L variant exhibit lower plasma concentrations of PCSK9 [4].
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 [3,7,11-13,17]. This function of PCSK9 helps to modulate LDL metabolism. Inhibition of PCSK9 results in increased numbers of LDL receptors on hepatocyte membranes [8] 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 [9]. Development of alternatives to the antibody-based PCSK9-inhibition strategy are the focus of multiple research projects [14].

References

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1. 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]

2. 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]

3. 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]

4. 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]

5. 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.

6. 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.

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

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

14. 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]

15. 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.

16. 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]

17. 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 04/03/2020. Accessed on 07/05/2021. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2388.