Protein engineers navigate toward more targeted therapeutics
New research on protein receptors could lead to breakthroughs in
improving drug delivery.

Date:
March 16, 2023
Source:
University of Minnesota
Summary:
Researchers uncovered the role of the third intracellular loop in
the G protein-coupled receptors' signaling mechanism, which could
lead to a more targeted approach to drug discovery and a paradigm
shift for new therapeutics.


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FULL STORY ==========================================================================
More than a third of FDA-approved drugs work by targeting a G
protein-coupled receptor, or GPCR. The human body has more than 800
types of GPCRs that provide cells with information about the external environment to calibrate responses.

Drugs that either block or activate GPCRs are used to treat a wide range
of diseases including hypertension, pain and inflammation. Most drugs
bind to the outside of the receptor, but this can result in adverse side effects since receptors often resemble one another.


==========================================================================
In a new study published in Nature, Sivaraj Sivaramakrishnan, a professor
in the College of Biological Sciences, along with graduate student Fred
Sadler and co-authors Michael Ritt and Yatharth Sharma, uncovered the
role of the third intracellular loop in the GPCR's signaling mechanism, suggesting the possibility of a more targeted approach to drug discovery
and a paradigm shift for new therapeutics.

"Typical GPCR drugs act as on or off switches for cellular signaling
outcomes," said Sivaramakrishnan. "Drugs that leverage the loop
effectively can act as signaling dimmer switches to more precisely control
drug responses." The authors developed new biochemical and biophysical
tools, combined with computational measurements by collaborators Ning Ma
and Nagarajan Vaidehi at the City of Hope Cancer Center. They tracked how
the third intracellular loop changes in shape, or conformation, through
the receptor signaling process. In a breakthrough for the field, their
data show that the loop acts as a kind of gate to ensure that receptors activate the correct type of G protein signaling at the right intensity.

"A key advantage of this loop is that it is highly unique, even among
closely related receptors, making it an outstanding drug target,"
said Sadler.

"Developing drugs through this newly discovered mechanism would allow for
far more targeted therapeutics." Funding was provided by the National Institutes of Health and the University of Minnesota Graduate School.

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========================================================================== Story Source: Materials provided by University_of_Minnesota. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Fredrik Sadler, Ning Ma, Michael Ritt, Yatharth Sharma, Nagarajan
Vaidehi, Sivaraj Sivaramakrishnan. Autoregulation of GPCR
signalling through the third intracellular loop. Nature, 2023;
DOI: 10.1038/s41586- 023-05789-z ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/03/230316154106.htm

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