Antitumor Steroids
443
site-directed
mutageneses,
hydrophobic
cluster analyses, motif-based searches for
homology with other proteins of known
structures, and crystallographic studies.
All HBDs are hydrophobic pockets, ex-
cept at subsites corresponding to polar
centers of cognate hormones; virtually,
amino acids of these binding pockets sur-
round the steroids. HBDs are somehow
flexible in order to accommodate various
ligands. Enlargement of a subsite results
from the conformational reorganization of
the whole HBD upon ligand binding: oc-
cupation of one subsite may modify the
flexibility at a second subsite indicating
that they respond to the ligand as a whole
entity. Subsites are flexible because HBDs
are composed of polypeptide segments
rich in amino acid residues with mobile
side chains (e.g. lysine, methionine, etc.).
Interaction of a steroidal hormone (or
any synthetic ligand) with its cognate
receptor depends upon several parameters
(size, shape, polarity of atoms within
the steroidal rings, etc.). Polar functions
located at the extremities of the steroidal
core (pos. 3 et 17) are of prominent
importance for the onset of a biological
function, as illustrated hereunder by the
binding of estradiol (E
2
) and the partial
antiestrogen hydroxytamoxifen (OH-Tam)
to the estrogen receptor (
α
-isoform).
Most important amino acids involved
in the binding of E
2
to the ER-HBD are
Glu353 and Arg394 on the one hand,
His524 on the other hand: Glu353 and
Arg394 interact with the C
3
phenolic group
of the hormone (H-bridge, participation of
an H
2
O molecule) while His524 interacts
with 17
β
oxygen (Fig. 3). As stated above,
location of E
2
within the HBD leads to a
displacement of H12 favoring the access of
coactivators to their binding site; virtually
H12 surrounds E
2
and shields the pocket
where it is locked from the environment
(‘‘closed conformation’’).
OH-Tam (Fig. 4) is a triphenylethylenic
derivative of prominent importance for
the treatment of ER-positive breast cancer;
aminoalkyl side chain of the compound is
responsible for its antiestrogenic (and cy-
tostatic/cytotoxic) activity. Phenolic group
of the drug (pos. 4) interacts with Glu353
and Arg394, as the C
3
phenolic group of E
2
.
O
AB
CD
O
O
C
O
O
O
HN
HO
HN
Glu353
H
N
O
O
NH
N
H
N
N
H
C
O
O
His524
Water
Arg394
NH
Fig. 3
Docking of E
2
in the ER
α
-HBD. The phenolic A-ring of E
2
is located in
the HBD by Glu353 and Arg394 and tethered by His524.
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