Page 8 - Grey_Matter_11_2021

SPECIALITY

7

behavior -- whereas eliminating
GPR158 activity in chronically
stressed mice made them resistant
to depression and the effects of
stress. Additionally, the activity of
GPR158 receptor has been also
linked to prostate cancer.

Historically, GPR158 hasn’t been
easy to study. It is called an “orphan
receptor” because scientists
haven’t yet identified the molecule
responsible for turning its signaling
function “on” in a manner similar
to flipping a switch. The receptor is
also considered unusual because, First author Dipak Patil, PhD, a “The microscope uses a beam of
in the brain, unlike most receptors staff scientist in the Martemyanov electrons instead of light to image
in its family, it exists in close laboratory, says solving the protein assemblies. The shorter
association with a protein complex structure provides many new wavelength of electrons compared
called the RGS signaling complex. insights. to light allowed us to visualize our
RGS is short for “regulator of G sample at near-atomic resolution,”
protein signaling” and it acts as a “I am thrilled to see the structure says structural biologist Professor
powerful brake on cellular signaling. of this unique GPCR. It is first Tina Izard, PhD. Patrick Griffin,
However, it has been unclear why of its kind, showing many new PhD, Scripps Research, Florida
GPR158 engages it. features and offering a path for drug scientific director, co-authored
development,” Patil says. the study, applying a structural
In the new study, solving the proteomic platform technology.
receptor’s structure offered many The challenge is now to use the
insights into how GPR158 works. information gleaned from the “The promise of Cryo-EM for
First, scientists found that it binds structure to inform the design achieving significant breakthroughs
RGS complex in the same way that of small molecule therapeutics in solving structures of biomolecules
many receptors typically engage to combat depression, is enormous. Our Institute is firmly
their conventional transducers, Martemyanov adds. committed to expanding Cryo-EM
leading to the idea that it employs microscopy, which is made possible
RGS proteins as means of He is now exploring several through the recent acquisition and
transducing its signal. Second, the possible approaches, including installation of a new microscope on
structure revealed that the receptor disrupting the two-part campus.”
exists as two interconnected copies arrangement, interfering with
of the GPR158 proteins stabilized engagement of RGS complex, The study was a collaboration
by phospholipids. or by specifically targeting the including researchers from
cache domain with small, drug-like Columbia University and Appu
“These are fat-related molecules molecular binders. Regardless Singh, PhD, a structural biologist at
that effectively staple the two of the road taken, availability the Indian Institute of Technology in
halves of the receptor together” of structural information should Kanpur.
Martemyanov explains. greatly facilitate drug development
efforts to treat depression, Story Source:
Finally, on the other side of the Martemyanov says. Materials provided by Scripps
receptor that faces outside of the Research Institute. Note: Content
cell, an unusual module called the This study was made possible by may be edited for style and length.
cache domain was revealed. The the latest technological advances
authors believe the cache domain in microscopy, including freezing Journal Reference:
serves as a trap for the molecules proteins at ultra-cold temperatures 1. Dipak N. Patil et al. Cryo-EM
that activate GPR158. Cache and examining their organization structure of human GPR158
domains have never been observed through the lens of powerful receptor coupled to the RGS7-
in these types of receptors before, microscopes, a technique called Gβ5 signaling complex.
demonstrating the unique biology of cryogenic electron microscopy, or Science, 2021 DOI: 10.1126/
this orphan receptor. Cryo-EM. science.abl4732

8 GREY MATTER NEWS