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[Biochemistry](https://durgical.com/en/biochemistry/) · Enzyme

# PCSK9

PCSK9 binds the LDL receptor and sends it to be destroyed; blocking it leaves more receptors and lowers LDL cholesterol sharply.

Updated 2026-11-01

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## Key facts

- A liver serine protease that cleaves itself once; afterwards it acts as a binding protein, not as an enzyme.
- It binds the LDL receptor EGF-A domain; the complex is internalised and the receptor is degraded in the lysosome instead of recycling.
- Gain-of-function variants cause familial hypercholesterolaemia; loss-of-function variants give low LDL and fewer heart attacks.
- SREBP-2 induces it together with the LDL receptor, so statins raise PCSK9.

**Also called**
Proprotein convertase subtilisin/kexin type 9

**EC number**
[3.4.21.-](https://www.enzyme-database.org/query.php?ec=3.4.21.-)

**Genes**
PCSK9

**Structure (PDB)**
[3BPS](https://www.rcsb.org/structure/3BPS)

## Structure

- Prodomain, subtilisin-like catalytic domain and a cysteine/histidine-rich C-terminal domain; the prodomain stays bound and blocks the active site.
- Structure 3BPS shows PCSK9 bound to the LDL receptor EGF-A domain.

## Regulation

- SREBP-2 raises its transcription (statins raise it too).
- It circulates in plasma and acts on receptors on the hepatocyte surface.

## Inhibitors and toxins

- Monoclonal antibodies (evolocumab, alirocumab)
- Small interfering RNA (inclisiran), which lowers its production in the liver

## Clinical notes

- PCSK9 inhibitors lower LDL by about 50–60% on top of a statin and reduce cardiovascular events.
- They are used in familial hypercholesterolaemia and very high risk when a statin is not enough.
- It was discovered in families with familial hypercholesterolaemia lacking LDLR or APOB variants.

## Drugs that act here

- [Evolocumab](https://durgical.com/en/pharmacology/evolocumab/)
- [Alirocumab](https://durgical.com/en/pharmacology/alirocumab/)

## Related conditions

- [Familial hypercholesterolemia](https://durgical.com/en/conditions/familial-hypercholesterolemia/)
- [Atherosclerosis and dyslipidaemia](https://durgical.com/en/conditions/atherosclerosis-and-dyslipidaemia/)
- [Myocardial Infarction (Heart Attack)](https://durgical.com/en/conditions/myocardial-infarction/)

## Related

- [LDL receptor](https://durgical.com/en/biochemistry/enzymes/ldl-receptor/)
- [LDL (low-density lipoprotein)](https://durgical.com/en/biochemistry/topics/ldl/)
- [HMG-CoA reductase](https://durgical.com/en/biochemistry/enzymes/hmg-coa-reductase/)
- [Lipoprotein metabolism](https://durgical.com/en/biochemistry/topics/lipoprotein-metabolism/)

## Test yourself

Think of the answer, then tap the question to see it.

## How does PCSK9 raise LDL cholesterol?

It sends the LDL receptor to lysosomal degradation: fewer receptors clear less LDL.

## Why do statins raise circulating PCSK9?

They activate SREBP-2, which induces both the LDL receptor and PCSK9.

## What do loss-of-function PCSK9 variants do?

Lifelong low LDL and less coronary disease.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: [PCSK9: Proprotein convertase subtilisin/kexin type 9 (human)](https://rest.uniprot.org/uniprotkb/Q8NBP7.txt) (UniProt, 2026); [PCSK9 gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/pcsk9/) (MedlinePlus, US National Library of Medicine, 2026); [3BPS: PCSK9:EGF-A complex](https://www.rcsb.org/structure/3BPS) (RCSB Protein Data Bank, 2026); [Cholesterol Medicines: MedlinePlus](https://medlineplus.gov/cholesterolmedicines.html) (MedlinePlus, US National Library of Medicine, 2026).

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Representative model, for educational purposes only.

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Source: https://durgical.com/en/biochemistry/enzymes/pcsk9/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/enzymes/pcsk9/