The key to the proper functioning of immune cells is the Chemokine receptor. The proteins called Chemokines bind to its receptor to regulate the behavior of white blood cells.
Their importance is known very well, but their activation mechanism remains poorly understood.
In a new study, scientists successfully decoded the activation mechanism of the CCR5 receptor, a member of this family implicated in several diseases such as HIV/AIDS, cancer, and the respiratory complications of COVID-19.
Stephan Grzesiek, a professor at the Biozentrum of the University of Basel, said, “Research on CCR5 began almost 25 years ago as part of the fight against AIDS. It is fundamental to the HIV infection mechanism and seems to be very important in many other pathological processes, notably in cancers and inflammatory diseases. However, to better exploit it for therapeutic purposes, we needed to understand, at an atomic level, how activation through its binding to chemokines works.”
Oliver Hartley of the Department of Pathology and Immunology at UNIGE Faculty of Medicine said, “to understand the entire process; it is necessary to make use of engineered chemokines that bind to receptors more stably than the natural ones. For this, we were able to exploit the molecules that we had discovered in our HIV drug research. And indeed, some of these variants over-activate the receptor while others block them entirely.”
The receptor works like a “lock and key” mechanism. A particular part of the chemokine structure should find a way into the CCR5 lock to actuate a change in the receptor, allowing it to trigger the activation and migration of white blood cells.
Oliver Hartley said, “The activation capacity of chemokines is determined by certain amino acids (protein building blocks) that must arrange themselves in a specific pattern. If this part of the chemokine adopts a straight shape, it succeeds in activating the receptor. But if the amino acids are changed, the molecule adopts a slightly different shape, which maintains a powerful bond with the receptor and prevents its activation. These small changes thus make the difference between receptor activators and inhibitors.”
- Polina Isaikina et al. Structural basis of activating the CC chemokine receptor 5 by a chemokine agonist. DOI: 10.1126/sciadv.abg8685