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

# Proteasome (26S, β5 subunit)

The proteasome is the cell's shredder for proteins tagged with ubiquitin. Myeloma drugs such as bortezomib block its cutting site.

Updated 2026-11-01

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## Key facts

- The 20S core is a stack of four rings of seven subunits (α7β7β7α7); the active sites face the inside of the chamber, so only unfolded proteins reach them.
- Three β subunits cut: β1 (caspase-like, after acidic residues), β2 (trypsin-like, after basic residues) and β5 (chymotrypsin-like, after hydrophobic residues).
- Each active site uses the N-terminal threonine of the β subunit as its nucleophile (a threonine protease).
- 19S regulatory caps bind polyubiquitin, remove it, unfold the substrate with ATPases and open the α-ring gate.
- Bortezomib, a boronic acid dipeptide, binds the β5 threonine reversibly and blocks chymotrypsin-like activity.

**Also called**
20S core particle, PSMB5, Multicatalytic protease

**EC number**
[3.4.25.1](https://www.enzyme-database.org/query.php?ec=3.4.25.1)

**Genes**
PSMB5

**Structure (PDB)**
[5LF3](https://www.rcsb.org/structure/5LF3)

## Structure

- 5LF3: the human 20S proteasome with bortezomib bound in the β5 sites (chain K shown, with the inhibitor in its active site).
- The boron atom of bortezomib bonds to the hydroxyl of the N-terminal threonine (Thr1) of β5.

## Regulation

- Gating by the 19S cap (ATP-dependent) and by other activators such as PA28.
- Interferon-γ induces immunoproteasome subunits (β1i, β2i, β5i) that make better peptides for MHC class I.

## Inhibitors and toxins

- Bortezomib (reversible, boronate)
- Carfilzomib (irreversible, epoxyketone)
- Ixazomib (oral, boronate)

## Clinical notes

- Proteasome inhibitors are a backbone of multiple myeloma treatment and are also used in mantle cell lymphoma and AL amyloidosis.
- Bortezomib often causes peripheral neuropathy; herpes zoster reactivation is also more frequent.

## Related conditions

- [Multiple myeloma](https://durgical.com/en/conditions/multiple-myeloma/)
- [Amyloidosis](https://durgical.com/en/conditions/amyloidosis/)

## Related

- [Ubiquitin–proteasome system](https://durgical.com/en/biochemistry/topics/ubiquitin-proteasome-system/)
- [Molecular chaperones and heat shock proteins](https://durgical.com/en/biochemistry/topics/molecular-chaperones-and-heat-shock-proteins/)
- [Protein structure and folding](https://durgical.com/en/biochemistry/topics/protein-structure-and-folding/)
- [Immunoglobulins (antibodies)](https://durgical.com/en/biochemistry/enzymes/immunoglobulins/)

## Test yourself

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

## Which proteasome subunit does bortezomib mainly inhibit?

The β5 subunit, which has chymotrypsin-like activity.

## Which amino acid is the catalytic nucleophile of proteasome active sites?

The N-terminal threonine of the active β subunits.

## Why do myeloma cells depend so much on the proteasome?

They make large amounts of immunoglobulin; blocking the proteasome lets misfolded protein build up, triggering ER stress and apoptosis.

## Why can folded proteins not be cut by the 20S core on its own?

The active sites are inside the closed chamber; the 19S cap must unfold the protein and open the gate.

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

Sources: [5LF3: Human 20S proteasome complex with Bortezomib at 2.1 Angstrom](https://www.rcsb.org/structure/5LF3) (RCSB Protein Data Bank, 2026); [PSMB5: Proteasome subunit beta type-5 (human)](https://www.uniprot.org/uniprotkb/P28074/entry) (UniProt, 2026); [PDB-101: Molecule of the Month: Proteasome](https://pdb101.rcsb.org/motm/166) (RCSB Protein Data Bank (PDB-101), 2026).

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Representative model, for educational purposes only.

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