Page 16 - Abacoa Community News - January '22

Page 16, Abacoa

The Scripps Research Institute News from page 15 “These are fat-related molecules that effectively staple the UF, Scripps Research Green-
two halves of the receptor together,” Martemyanov explains.
Scientists at Scripps Finally, on the other side of the receptor that faces outside Light Integration For Florida
Research, Florida have of the cell, an unusual module called the cache domain was
determined the near- revealed. The authors believe the cache domain serves as a Science Powerhouse
atomic-scale structure trap for the molecules that activate GPR158. Cache domains
of an unusual brain-cell have never been observed in these types of receptors before, The University of Florida (UF) and California-based
receptor called GPR158, demonstrating the unique biology of this orphan receptor. Scripps Research have signed a definitive agreement to
which has been linked to First author Dipak Patil, Ph.D., a staff scientist in the welcome the Florida branch of the science powerhouse
depression and anxiety. Martemyanov laboratory, says solving the structure provides into the research arm of UF’s academic health center – a
The structural study many new insights. “I am thrilled to see the structure of this step aimed at accelerating the translation of basic scientific
reveals both the receptor unique GPCR. It is first of its kind, showing many new features discoveries into clinical advances that benefit human health
and its regulating and offering a path for drug development,” Patil says. in the state and beyond. The operational transition will begin
compl ex, advancing The challenge is now to use the information gleaned this week.
understanding of basic cell from the structure to inform the design of small molecule
receptor biology. It also Cryo-EM cartoon rendition therapeutics to combat depression, Martemyanov adds.
enables work on potential of the structure of a brain He is now exploring several possible approaches,
therapeutics designed to receptor linked to depression, including disrupting the two-part arrangement, interfering
block GPR158 as a strategy shown with its signaling with engagement of RGS complex, or by specifically
for treating depression, complex. The assembly is targeting the cache domain with small, drug-like molecular
anxiety and possibly other called GPR158-RGS7-G5. binders. Regardless of the road taken, availability of
mood disorders. The GPR158 protomers are structural information should greatly facilitate drug
In the study, published shown in green and raspberry development efforts to treat depression, Martemyanov says.
Nov. 18 in the journal colors, RGS7 in blue and G5 This study was made possible by the latest technological
Science, the researchers used in orange. The lipid bilayer advances in microscopy, including freezing proteins at
ultracold, single-particle is gray. ultra-cold temperatures and examining their organization
electron microscopy, or through the lens of powerful microscopes, a technique
cryo-EM, to map, at a resolution of about a third of a called cryogenic electron microscopy, or Cryo-EM.
billionth of a meter, the atomic structure of GPR158, both “The microscope uses a beam of electrons instead of The integration is intended to celebrate and strengthen
on its own and when bound to a group of proteins that light to image protein assemblies. The shorter wavelength ongoing research at Scripps Florida, which has a stellar global
mediate its activity. of electrons compared to light allowed us to visualize our reputation, while leveraging opportunities to explore avenues
“We’ve been studying this receptor for more than 10 sample at near-atomic resolution,” says structural biologist of mutual interest and providing Scripps with a strong clinical
years, and have done a lot of biology on it, so it’s really Professor Tina Izard, Ph.D. partner. The goal? To build on the excellent scientific work
gratifying to see for the first time how it’s organized,” says Patrick Griffin, Ph.D., Scripps Research, Florida taking place to more expediently unlock clinical advances
lead author Kirill Martemyanov, Ph.D., Professor and Chair scientific director, co-authored the study, applying a that improve outcomes for patients in the state and around
of the Department of Neuroscience at the Scripps Research. structural proteomic platform technology. “The promise of the world, officials from both organizations said.
Clinical depression, also called major depressive Cryo-EM for achieving significant breakthroughs in solving “We are excited to work collaboratively with our
disorder, is estimated to affect roughly 20 million people structures of biomolecules is enormous. Our Institute is colleagues at Scripps to rapidly take discoveries made at
in the United States in any given year. Current treatments firmly committed to expanding Cryo-EM microscopy, the bench to the bedside, where they can have the most
work on other known receptors, including monoamine, which is made possible through the recent acquisition and benefit to humanity,” said David R. Nelson, M.D., senior
but don’t always work well for all people and alternative installation of a new microscope on campus.” vice president for health affairs at UF and president of UF
options are needed. The study was a collaboration including researchers from Health, the university’s academic health center. “We are
Martemyanov and his team found in a 2018 study that Columbia University and Appu Singh, Ph.D., a structural looking forward to cultivating a culture of innovation that
GPR158 is present at unusually high levels in the prefrontal biologist at the Indian Institute of Technology in Kanpur. will extend from the outstanding science already underway.”
cortex of people diagnosed with major depressive disorder In addition to professors Martemyanov, Griffin, Izard As part of the agreement, Scripps will transfer all assets
at the time of their death. They also found that exposing and Singh, and Staff Scientist Patil, the authors of the associated with the 30-acre Scripps Florida campus in Jupiter,
mice to chronic stress increased levels of this receptor study, “Cryo-EM structure of human GPR158 receptor situated within Palm Beach County’s innovation corridor –
in the mouse prefrontal cortex, leading to depression- coupled to the RGS7-Gβ5 signaling complex,” include property, buildings, equipment and adjacent 70-acre tract to
like behavior – whereas eliminating GPR158 activity in Thibaut Laboute, Timothy Strutzenberg and Scott Novick the University of Florida. The campus, one of the top National
chronically stressed mice made them resistant to depression of Scripps Research, Florida; Shikha Singh and John Hunt Institutes of Health-supported research centers in the state,
and the effects of stress. Additionally, the activity of of Columbia University; and Xingyu Qiu, Di Wu, and Carol includes more than 40 faculty-led laboratories supported by
GPR158 receptor has been also linked to prostate cancer. Robinson of the University of Oxford. a 500-member team dedicated to understanding an array of
Historically, GPR158 hasn’t been easy to study. It is The research was funded by the National Institutes of illnesses and seeking to generate effective treatments.
called an “orphan receptor” because scientists haven’t yet Health (MH105482) and supported by the National Cancer In addition, UF and UF Health have committed to work
identified the molecule responsible for turning its signaling Institute’s National CryoEM Facility at the Frederick with Scripps Florida leadership to immediately invest in the
function “on” in a manner similar to flipping a switch. National Laboratory for Cancer Research. new entity by hiring additional faculty; these new recruits
The receptor is also considered unusual because, in the Image courtesy of Martemyanov lab,
brain, unlike most receptors in its family, it exists in close Scripps Research Florida. The Scripps Research Institute News on page 17
association with a protein complex called the RGS signaling
complex. RGS is short for “regulator of G protein signaling”
and it acts as a powerful brake on cellular signaling.
However, it has been unclear why GPR158 engages it.
In the new study, solving the receptor’s structure offered
many insights into how GPR158 works. First, scientists
found that it binds RGS complex in the same way that many
leading to the idea that it employs RGS proteins as means NoN-Toxic cancer immunotherapy
receptors typically engage their conventional transducers,

of transducing its signal. Second, the structure revealed
that the receptor exists as two interconnected copies of the
GPR158 proteins stabilized by phospholipids. Available NoW
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