Hungry or full: It comes down to the atomic details
Insight into the molecular structure of an appetite-regulating cell
receptor

Date:
September 27, 2021
Source:
Charite' - Universita"tsmedizin Berlin
Summary:
A protein - measuring just a few nanometers in size - acts as a
molecular switch with a crucial role in determining whether we
feel hungry or full.

By determining of the protein's 3D structure, researchers were
able to visualize the molecular structures of the hormones with
which this protein -- melanocortin 4 receptor (MC4R) -- interacts.



FULL STORY ==========================================================================
A protein -- measuring just a few nanometers in size -- acts as a
molecular switch with a crucial role in determining whether we feel
hungry or full. By determining of the protein's 3D structure, researchers
from Charite' - - Universita"tsmedizin Berlin were able to visualize
the molecular structures of the hormones with which this protein -- melanocortin 4 receptor (MC4R) - - interacts. Writing in Cell Research,
the researchers report that this enabled them to describe the molecular mechanisms involved in the receptor's activation and inhibition. These
new findings could stimulate the development of optimized drugs to treat patients with severe overweight and obesity patients.


========================================================================== Studies exploring the nature of weight control 'switches' are more
important than ever. We need to be able to treat genetic disorders that
result in an inability to feel satiety after eating and which, even in
young sufferers, cause severe and difficult-to-treat obesity. At the same
time, obesity is one of the most pressing global challenges. Estimates
suggest that 1.6 billion adults and 650 million children worldwide are classified as overweight or obese. The condition is associated with
an increased risk of comorbidities such as cardiovascular disease and
diabetes mellitus. Steadily increasing incidence rates and long-term consequences are driving global research efforts to decipher the
mechanisms of appetite regulation at the molecular and ultimately at the
atomic level. In addition to exploring the impact of genetic defects on appetite and hunger, research efforts also focus on finding potential
targets for drug interventions.

In their recently published study, the team led by Dr. Patrick Scheerer,
Head of Protein X-ray Crystallography and Signal Transduction (Scheerer
Lab) at Charite''s Institute of Medical Physics and Biophysics, focused on
one of the key players in hunger (and therefore weight) control in humans:
the melanocortin 4 receptor (MC4R). Primarily found in the brain, this
receptor protein is controlled by hormones that produce important satiety signals by binding to it. Activation of MC4R by stimulating hormones
(a-/-MSH) results in the feeling of satiety. Conversely, inhibition by
the hormone's natural antagonist, known as Agouti-related protein (AgRP), results in increased hunger feeling. Genetic defects resulting in the functional impairment of this protein 'switch' often led to mild or even
severe obesity in humans. Prof. Dr. Peter Ku"hnen, physician-scientist
at the Institute of Experimental Pediatric Endocrinology, specializes
in the treatment of patients with genetically induced impairments in the transduction of satiety signals. As part of his search for new treatment options for these types of obesity, the endocrinology specialist has
devoted extensive efforts to studying the signaling pathways underlying
human body weight regulation. He has also explored mutations in the genes encoding the relevant cellular messengers and receptors and analyzed the potential of drugs that might be able to replace individual messengers.

The drug-based treatment of pathologically increased appetite continues
to face the same challenge: "To date, all of these pharmacological interventions have been dogged by side effects. These range from
abnormal darkening of the skin - - the hormone melanocortin also being responsible for skin and hair pigmentation -- to cardiovascular events,"
says Prof. Ku"hnen, who was also involved in the current study and whose
work supporting the development of new, low-side-effect drugs was awarded
the Paul-Martini Prize in 2020. "The reason for these undesirable side
effects lies in the nature of the currently available drugs," explains
study lead Dr. Scheerer. He adds: "Instead of addressing a single target,
they are usually directed at a range of receptors from the same family
which, unfortunately, play different roles in our bodies.

The more we know about the interactions between the components involved,
the easier it will be to target interventions." The teams led by
Dr. Scheerer and Prof. Ku"hnen work closely together. In addition to
sharing a common interest in the translation of research findings into
clinical practice, their endeavors also complement the work of the
DFG-funded Collaborative Research Center 'Structural Dynamics of GPCR Activation and Signaling' at Leipzig University.

Charite' is involved in four of the Collaborative Research Center's subprojects.

As part of the current study, the researchers were able to elucidate
and visualize the 3D molecular structure of the hormone receptor MC4R,
a member of the G-protein-coupled receptor (GPCR) family. Given that the protein's tiny size is expressed in nanoscale dimensions, conventional
optical methods were inadequate for the task. "Using a state-of-the art
imaging technology known as cryo-electron microscopy, we were able to
visualize the receptor's three- dimensional structure at a resolution of
around 0.26 nanometers" says the study's first author, Nicolas Heyder,
a researcher at the Institute of Medical Physics and Biophysics. "We
visualized the structures of two receptor-effector complexes, both of
which contain the G-protein which is coupled to the receptor inside the
cell. The differences between the two complexes are due to their being
bound to two different hormones, namely setmelanotide and NDP-a-MSH. Both received their marketing authorization in the past two years, and both are stabilized by a calcium ion in the hormone binding pocket of MC4R." In addition, the researchers found that the two receptor structures showed
minor yet important differences in the way they bound both the drugs and
the G- protein. "These molecular details provide important information on
why and how various ligands -- i.e., messenger molecules -- exert specific effects on different MC4R signaling pathways. For a pharmacological intervention, this is of major importance," says Nicolas Heyder.

This essential groundwork regarding the nature of the tiniest cell
components would not have been possible without cryo-electron microscopy
and many years of experience in establishing cell culture-based protein production. Both have been subject to ongoing optimization at Charite',
thanks to collaborations with world-leading laboratories and experts,
including Chemistry Nobel Laureate Prof. Dr. Brian Kobilka, a Stanford professor and an Einstein Visiting Fellow at the Berlin Institute of
Health (BIH) at Charite'.

In their study results, the researchers describe previously unknown
details regarding the mechanisms underlying melanocortin 4 receptor
function: how it is activated, how it is blocked, and how the interaction between a hormone and the receptor protein produces a signal inside
the cell. "We are now able to identify the smallest differences in the interactions between receptors and hormones. These could prove important
for the continued refinement of new drugs which would previously have
been associated with side effects," says Dr.

Scheerer. He adds: "Now that the precise structure of the hormone-binding pocket is known, it can be targeted directly." This is key to the
translational use of knowledge on both the endocrinological aspects
(in this case hormone regulation) and structural characteristics of
interacting proteins.

The research team was able to show that how a previously known
receptor- deactivator -- or antagonist -- binds to the receptor almost identical to the receptor-activating agonist, with only one significant difference. "This difference pinpoints the precise site that blocks the receptor, and which contains a sensitive switch that is responsible
for activating the protein," explains Dr. Scheerer. The researchers
hope that additional research to improve their understanding of the
MC4R signaling system will enable them to identify potential sites
for targeted interventions. As a next step, the researchers hope to
understand how additional factors might be controlling the receptor
at the molecular level. Some of the directly interacting factors have
already been identified. Their impact, however, remains to be elucidated.

About this study This research was made possible thanks to funding
provided by the German Research Foundation (DFG) through the Collaborative Research Center 1423 (CRC 1423) 'Structural Dynamics of GPCR Activation
and Signaling'. The research received additional support through the
Excellence Cluster 'Unifying Systems in Catalysis (UniSysCat)', the Collaborative Research Center 'CRC 1365' (DFG) and the Berlin Institute
of Health (BIH) at Charite'.

========================================================================== Story Source: Materials provided by
Charite'_-_Universita"tsmedizin_Berlin. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Heyder N et al. Structures of active melanocortin-4
receptor-Gs-protein
complexes with NDP-a-MSH and setmelanotide. Cell Research, 2021
DOI: 10.1038/s41422-021-00569-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210927110505.htm

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