5 research outputs found
Molecular Dynamics Simulations for Human CAR Inverse Agonists
Constitutive androstane receptor (CAR), along with pregnane
x receptor
(PXR), is an important metabolic sensor in the hepatocytes. Like all
other nuclear receptors (NRs), CAR works in concert with coregulator
proteins, coactivators, and corepressors which bind to the NRs. The
main basis for the receptor to distinguish between coactivators and
corepressors is the position of the C-terminal helix 12 (H12), which
is determined by the bound NR ligand. CAR, having constitutive activity,
can be repressed or further activated by its ligands. Crystal structure
of human CAR bound to an agonist and a coactivator peptide is available,
but no structural information on an inverse agonist-bound human CAR
and a corepressor exists. In our previous molecular dynamics (MD)
studies, no corepressor peptide was included. Therefore, probably
due to the strong interactions which keep the relatively short H12
of CAR in the active position, the structural changes elicited by
inverse agonists were very subtle, and H12 of CAR seemed to more or
less retain its active conformation. Here, we have run a series of
MD simulations to study the movement of H12 in the presence of both
activating and repressing ligands as well as a corepressor peptide.
The presence of the corepressor on the coregulator surface of CAR
induced a clear shift of H12 of the inverse agonists-bound CAR. In
general, H12 moved toward H10 and not away from the ligand binding
domain, as seen in some other NRs. However, H12 of CAR is short enough
that this movement seems to be adequate to accommodate the binding
of the corepressor