442
Antitumor Steroids
COOH
Dimerization
Zn Finger 1
Zn Finger 2
Nuclear localization
Ligand binding
DNA binding
AF-2
AF-1
Hsp90 binding
501
535
a.a 1
NH
2
185
250
311
551
595
185
205
221
245
256
263
A/B
C
D
F
E
Fig. 2
ER
α
domains. ER
α
is composed of six molecular domains, which allow it to localize
into the nucleus, dimerize, bind to ligand and DNA, and regulate the transcription through
hormone-independent (AF-1) and hormone-dependent (AF-2) mechanisms.
Sp1 etc.). Transcription requires nuclear
proteins (coactivators) that are recruited
by the DNA-bound receptors. Coactivators
vary among tissues eventually giving rise
to tissue-specifc responses to a given hor-
monal stimulation. Antagonists repress
transcription by a reverse process (block-
ade oF association with response elements
and/or recruitment oF corepressors).
A±1 expression is regulated by growth
Factors via classical signal transduction cas-
cades while A±2 (and apparently A±-2b)
is entirely dependent on the association
oF the receptor with the ligand. Under
most conditions, the ligand induces a
Functional synergism between A±1 and
A±2 due to major reorganization in the
tertiary structure oF the receptor. HBD con-
tains 12
α
-helixes (H1–H12) Folded into a
3-layered antiparallel
α
-helical sandwich.
The central core oF the HBD layer con-
tains 3
α
-helixes (H5/6, H9, and H10)
sandwiched between 2 additional layers
oF helixes composed oF H1–4, H7, H8,
and H11; it is flanked by H12, which
contains the core region oF A±2. Ago-
nists elicit a receptor conFormation oF
the HBD so that H12 is aligned over
the hormone binding cavity; the Forma-
tion oF a salt bridge between H4 and
H12 stabilizes the reposition oF the latter.
This main conFormational change results
in the emergence oF a specifc binding
site (a groove) For a consensus
α
-helical
motiF (LxxLL, ‘‘NR’’ box) Found in coac-
tivators. Antagonists sterically interFere
with H12 positioning thereby preventing
recruitment oF coactivators and Favoring
binding oF corepressors.
2.2
Conformational Changes of Ligand-binding
Domains Induced by Agonists or
Antagonists
HBD
structure
oF
each steroidal
hor-
mone receptor has been established by
amino acid labeling with reactive ligands,
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