ISSN 1022-7954, Russian Journal of Genetics, 2007, Vol. 43, No. 3, pp. 234–240. © Pleiades Publishing, Inc., 2007.
Original Russian Text © J.V. Nikolenko, A.N. Krasnov, 2007, published in Genetika, 2007, Vol. 43, No. 3, pp. 308–316.
OF NUCLEAR RECEPTORS
The classic pathway of signal transduction from the
environment into the cell is an intricate multistep pro-
cess that starts from the interaction of a ligand with its
receptor on the cell membrane. As a result, the receptor
triggers a cascade of events in the cell cytoplasm and,
eventually, speciﬁc transcription factors regulate the
expression of nuclear gene in a certain way. Transcrip-
tion factors of the nuclear receptor superfamily have a
unique structure and, consequently, utilize another
strategy. Nuclear receptors each harbor the domains
responsible for the receptor function, DNA binding,
and effects on transcription in one protein molecule.
Thus, it takes only one step to respond to an external
stimulus by changes in gene expression in the cell .
Nuclear receptors form one of the largest transcrip-
tion factor families (superfamilies) in Metazoa .
A characteristic structural feature is that nuclear recep-
tors possess two conserved domains: a DNA-binding
domain (DBD) and a ligand-binding domain (LBD),
which is close to the C end. The two domains are linked
together by a ﬂexible hinge (Fig. 1a). DBDs are highly
conserved among different nuclear receptors and have
two zinc ﬁnger motifs containing four cysteine residues
each. The ﬁrst zinc ﬁnger contains a so-called P-box of
ﬁve residues, which is responsible for speciﬁc DNA
binding. The second zinc ﬁnger displays a relatively
weak capability of dimerization, allowing DBD to form
dimers in the presence of target DNA. LBD is con-
served to a lesser extent and harbors the major dimer-
ization region, which allows molecules of different
receptors to form dimers, thereby substantially expand-
ing the range of potential DNA targets and regulatory
functions. LBD consists of 11–13
which form a hydrophobic pocket for ligand binding.
The N-terminal AF-1 activation domain (
function 1) is capable of ligand-independent function-
ing, while the AF-2 domain, which is at the C end of
LBD, often functions in a ligand-dependent manner.
Detailed structural and molecular studies showed that
ligand binding induces a conformational transition of
LBD into an active state:
-helix 12 turns to a position
such that the AF-2 domain becomes capable of recruit-
ing transcriptional coactivators . Certain nuclear recep-
tors have only some of the above domains; the other
domains were presumably lost during evolution .
MECHANISMS OF NUCLEAR RECEPTOR
INTERACTIONS WITH DNA AND LIGANDS
AND THE EFFECTS OF NUCLEAR RECEPTORS
When ligands are absent from the cell, free nuclear
receptors occur in the cytoplasm or in the nucleus. The
ligands of nuclear receptors are a broad range of small
Structure and Mechanisms of Action
J. V. Nikolenko
and A. N. Krasnov
Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334 Russia;
fax: (495) 135-41-05; e-mail: email@example.com
Center of Medical Research, University of Oslo, Moscow, 119334 Russia
Received May 3, 2006
—Nuclear receptors are a superfamily of conserved transcription factors with a unique domain struc-
ture. Nuclear receptors play an important role in the regulation of ontogeny, sexual maturation, and cell differ-
entiation, as well as in various metabolic processes. Owing to the speciﬁcs of hormonal signaling,
provides a promising model subject for studying the function and regulation of nuclear receptors.
The review considers modern data on the molecular structure of nuclear receptors and the mechanisms of their
interactions with ligands and transcription cofactors. The known functions of nuclear receptors in regulating
embryo development and metamorphosis in
are described in detail.
AF-1 LBD AF-2
(a) Structure and (b) mechanism of action of nuclear
receptors . See text for comments.