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Welcome everyone to Chapter 6 of
this short talk series on
nuclear receptors
therapeutic targets.
In this chapter,
we will build on
the structural and
molecular features of
nuclear receptor
activity that we
have discussed in the
last two chapters to
capture the binding of
ligands and the
activation mechanisms.
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As discussed in Chapter 3,
the canonical ligand binding
site of nuclear receptors
is located in a cavity within
the ligand binding domain.
This binding site is typically
quite hydrophobic and it can
have a large volume for
some nuclear
receptors like LRH-1,
PPAR, and PXR.
But it can also be blocked by
bulkier minor acids
like NR4A receptors.
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Ligand binding to the canonical
ligand binding pocket
or to other epitopes for
some nuclear receptors
affects the conformation of
the ligand binding domain and
especially the
position of Helix 12.
We have seen in the last
chapter that the position of
Helix 12 is critical
for the information
of the co-activator
binding surface and that
the mechanism of nuclear
receptor activation
by ligands thus
involves the ligand induced
stabilization of
Helix 12 to generate
a binding surface for
the coactivator and
the subsequent recruitment
of a coactivator complex.
Here you can see the PPARgamma
in various conformations and
with diverse positions of
Helix 12 depending
on the bound ligand.
These multiple possible
conformations underline
the dynamic nature of
the ligand binding domain and
the activation mechanism.
On the top left you see the
ligand-free APO structure
with Helix 12 oriented
away from the ligand
binding domain.
The following two structures in
the top row comprise ligands
that do not activate
the receptor
which can be seen from
the position of Helix 12
still oriented away from the
ligand binding domain and
the other five
conformations bind
activating ligands
and comprise Helix 12
bound to the ligand
binding domain core
in various active
conformations and
positions that vary slightly
but all enable
coactivator recruitment.
When we have a closer look at
