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Vitamin D receptor visualized for the first time in 3D

By R&D Editors | January 24, 2012

/sites/rdmag.com/files/legacyimages/RD/News/2012/01/VitaminD.jpg

click to enlarge

Representation of the 3D architecture of two receptors, VDR (vitamin D receptor) and its partner RXR (retinoid X receptor, a vitamin A derivative), after 3D reconstruction from images of individual particles. In mauve, the experimental 3D map obtained by cryo-EM. Specific binding sites on the DNA fragment are shown in green and red. The DNA binding domain (DBD) and ligand binding domain (LBD) are also featured. Image: IGBMC (CNRS/Inserm/Université de Strasbourg)

For
the first time, a team from the Institut de Génétique et de Biologie
Moléculaire et Cellulaire (IGBMC, Université de Strasbourg/CNRS/Inserm)
has obtained a high-resolution, full 3D image of a small but vital
molecule locked up within our cells: the vitamin D receptor (VDR).

Published on Jan. 18, 2012, in The EMBO Journal,
this study provides key information on the 3D structure and action
mechanism of the receptor at the molecular scale. This data is crucial
to pharmaceutical research, since VDR is involved in numerous diseases
such as cancer, rickets and type 1-diabetes.

A
member of what biologists call “the large family of nuclear receptors”—or proteins active in the nucleus of cells—along with “steroidal”
receptors (sexual hormone receptors, etc.), the vitamin D receptor (VDR)
plays an important role in regulating the expression of genes involved
in various vital biological functions (cell growth, bone mineralization,
etc.).

Until
now, researchers had only been able to study two parts of this receptor
at close range: the DNA interaction region and the vitamin D binding
domain. These two parts had been produced in the laboratory and their
structure studied individually using crystallography techniques.
However, this method does not lend itself to mapping VDR in its entirety
since the receptor is difficult to crystallize.

To
meet this challenge, which has called upon the resources of many
researchers around the world for more than 15 years, the teams led by
Bruno Klaholz and Dino Moras, both CNRS senior researchers at IGBMC,
resorted to an innovative technique: cryo-electron microscopy (cryo-EM),
which requires a next-generation “high-resolution” electron microscope.
This technological marvel makes it possible to observe biological
objects at the molecular and even atomic scale. In France, the first
such EM was installed at IGBMC(2) in 2008. Before this work was carried
out, it was widely assumed that studying VDR with cryo-EM was
impossible. In fact, until now, the smallest molecules observed using
this technique weighed more than 300 kilodaltons (kDa), or even
several thousand kDa, in other words much more than the VDR, which
weighs 100 kDa and measures a mere 10 nm (10 x 10-9 m).

In concrete terms, Klaholz and his colleagues produced large quantities of human VDR in Escherichia coli
bacteria (one of the most widely used models in biology to produce
proteins) in the laboratory. They then isolated the receptor in a
physiological solution containing water and a little salt. The sample
containing the VDR was then flash-frozen by immersion in liquid ethane,
allowing extremely rapid cooling (within a fraction of a second the
sample drops from 25 C to around -184 C). Finally, the team had to take
20,000 photographs of VDR particles in different orientations, using the
microscope. Once aligned and combined via a computer program, these
images finally provided a full 3D reconstruction of the VDR.

This
image supplies new information on how the receptor works. It reveals
that the VDR and its partner RXR (retinoid X receptor, a vitamin A
derivative) form an open architecture, with the vitamin D binding domain
almost perpendicular to the DNA binding domain (see figure below). This
structure suggests cooperation between both domains, which could act
together to induce highly-precise regulation of target gene expression.

This
pioneering work opens the way to the elucidation of several other,
still poorly understood vital nuclear receptors.  In particular,
biologists are now looking at using cryo-EM to reveal the structure of
steroidal receptors.

Structure of the full human RXR/VDR nuclear receptor heterodimer complex with its DR3 target DNA

SOURCE

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