Apoptosis
Apoptosis is a type of cell death
that removes diseased and unwanted
cells from the body.
Mitochondria play a central role in this process.
Apoptotic proteins released from the
mitochondria destroy the cell.
On the surface of mitochondria
three groups of proteins
regulate apoptosis.
The initiator
pore-forming
and guardian proteins.
The fate of a cell is
determined by an interplay of these
three proteins.
The interaction between
these proteins is mediated by BH 3 domains
and BH 3 binding grooves.
An initiator binds a pore-forming protein.
This activates pore-forming protein
revealing a hidden domain.
Acting as a
safeguard against apoptosis
guardian protein binds activated pore-forming protein.
Initiators also then compete for
guardian protein, releasing pore-forming protein.
Released pore-forming proteins
combine to form dimers.
The pore-forming proteins gather and
create holes in the outer mitochondrial membrane.
Proteins are released that
drive the cell towards apoptosis.
Venetoclax
Venetoclax is a potent drug that
causes cancer cells to undergo apoptosis.
In some forms of cancer
such as chronic lymphocytic leukaemia
an abundance of
guardian proteins on the outer
mitochondrial membrane keeps
cancer cells alive.
In cancer excess guardian
proteins stop the pore-forming proteins
from puncturing the membrane.
Venetoclax is designed to bind to guardian
protein and activate apoptosis.
The drug releases initiator and
pore-forming proteins.
Released pore-forming proteins combine
and create holes in the
outer mitochondrial membrane.
Proteins spill out of the mitochondria
that drive venetoclax-treated cells
to be selectively killed by apoptosis.