How a Cell Receptor and Protein Work Together to Select Specific Molecules

Greg Howard
17th April, 2025

How a Cell Receptor and Protein Work Together to Select Specific Molecules

Cryo-EM structures of the HCAR1-Gi1 complex with its specific agonist CHBA (a) and in an unbound state (b), alongside the HCAR2-Gi1 complex with specific agonists MK-1903 (c) and SCH900271 (d), reveal the structural basis for ligand recognition and subtype selectivity between the two receptors.

Image adapted from: Pan et al. / CC BY (Source)

Key Findings

  • Researchers at Yangzhou University uncovered detailed structures of HCAR1, a receptor important in cancer cell growth
  • They discovered that HCAR1 and its related receptor HCAR2 bind activating molecules differently, offering specific targets for cancer drugs
  • These findings lay the groundwork for designing new therapies that can effectively block HCAR1, potentially slowing cancer progression
Hydroxycarboxylic acid receptor 1 (HCAR1), also known as the lactate receptor, plays a crucial role in various bodily functions, including lipid metabolism, neuroprotection, and inflammatory responses[1]. Understanding how HCAR1 operates is essential, especially since it is highly expressed in many cancer cells, influencing their metabolism and defense mechanisms. Targeting HCAR1 could offer new avenues for cancer treatment, but the exact ways it sends signals within cells were not fully understood. A recent study conducted by researchers at Yangzhou University used advanced cryo-electron microscopy (cryo-EM) to capture detailed structures of human HCAR1 and its closely related receptor HCAR2. They examined these receptors bound to specific molecules that activate them, as well as in their inactive form. This structural information provides a clearer picture of how HCAR1 recognizes different molecules, becomes activated, and interacts with G proteins inside the cell. The researchers discovered key differences in how HCAR1 and HCAR2 bind to their respective activating molecules. By identifying the specific areas on the receptors that determine which molecule they bind to, the study clarifies how each receptor functions uniquely. This is particularly important because HCAR1’s role in cancer cell metabolism means that drugs targeting it could effectively disrupt cancer growth without affecting other similar receptors. To achieve these insights, the team combined cryo-EM data with experiments that altered specific parts of the receptors and observed the resulting changes in function. These methods allowed them to pinpoint which parts of HCAR1 are critical for its activity and how it selectively binds to certain molecules. Such detailed understanding lays the groundwork for designing new drugs that can specifically target HCAR1, potentially leading to more effective cancer therapies with fewer side effects. This research builds on prior findings about lactate's role in the body. Lactate is not just a byproduct of metabolism but also serves as a signaling molecule coordinating between different cells and tissues[2][3][4]. The study of HCAR1 fits into this broader understanding by revealing how lactate receptors like HCAR1 can regulate vital processes such as energy metabolism and inflammatory responses[2]. Furthermore, since lactate metabolism is linked to conditions like diabetes and cancer[3], targeting its receptors could influence these diseases by altering how cells use energy and respond to stress[4]. By providing a detailed map of HCAR1’s structure and its interaction with activating molecules, this study from Yangzhou University offers significant advancements in our understanding of cellular metabolism and signaling. It opens up new possibilities for developing targeted therapies that can modulate lactate signaling pathways, which could have widespread implications for treating cancer and other metabolic disorders.

MedicineBiotechBiochem

References

Main Study

1) Structures of G-protein coupled receptor HCAR1 in complex with Gi1 protein reveal the mechanistic basis for ligand recognition and agonist selectivity

Published 15th April, 2025

https://doi.org/10.1371/journal.pbio.3003126

Related Studies

2) Lactate metabolism in human health and disease.

https://doi.org/10.1038/s41392-022-01151-3

3) Comprehensive review on lactate metabolism in human health.

https://doi.org/10.1016/j.mito.2014.05.007

4) Lactate as a fulcrum of metabolism.

https://doi.org/10.1016/j.redox.2020.101454


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