How immune cells are activated

T lymphocyte immune cells protect our body against pathogens. Chemokine signalling molecules direct these T cells to the site of infection where they help to eliminate the invading pathogens. This process is mediated by chemokine receptors on the surface of the T cells. One of the best-known chemokine receptors is CCR5. CCR5 is an important target for anti-HIV drugs since it is hijacked by the HI-Virus to enter the cells. However, CCR5 is also involved in many other immune processes where it plays a decisive role, for example, in the context of Covid-19 or cancer.

Activated by certain chemokines only

Several structures of the inactive CCR5 receptor had been solved in the past. They have provided insights into the mode of action of HIV entry inhibitors, which prevent the AIDS virus from entering the T cell. However, until now, the activation mechanism of CCR5 had not been elucidated. A detailed picture of this process has now been obtained by a collaboration between researchers at the Paul Scherrer Institute PSI, the Biozentrum at the University of Basel, and the University of Geneva. In the journal Science Advances, they explain why only some chemokines activate the CCR5 receptor, while others simply block it.

A deep insertion

CCR5 belongs to the large family of G protein-coupled receptors. They can be thought of as “cellular intercoms”: they are installed in a wall (the cell membrane), and someone (a chemical substance) rings from the outside to transmit information to the inside (the cytoplasm). In the case of CCR5, only particular chemokines are able to “ring” the CCR5 and activate the cellular machinery that, for example, triggers the migration of T cells to the infection site. The authors of this work have now discovered that the ability of chemokines to activate CCR5 depends on the molecular structure of the N-terminal region of the chemokine.

“Both the sequence and the structure of the first residues in the N-terminus of the chemokine control how it inserts into the binding pocket of the CCR5 receptor,” explains PSI researcher Ching-Ju Tsai. “Certain amino acids at key positions of the chemokine stabilize a straight conformation of the N-terminus that allows a deeper insertion into the receptor. This results in conformational changes within CCR5 that turn on the cellular machinery.” Other chemokines with differing amino acid types at these positions induce instead a collapsed N-terminus that cannot insert deeply enough into the receptor to activate it. Thereby the receptor gets blocked in an inactive state.

Impact for drug development

The various types of chemokines and chemokine receptors share similar sequences and architectures. Yet tiny structural differences in either the receptor or the chemokine determine which ligand activates which receptor. “We were interested in understanding the interplay between chemokines and the CCR5 receptor at the atomic level,” summarizes Xavier Deupi, one of the leading authors at PSI. “CCR5 has been relevant in AIDS research for a long time, but it is also involved in other diseases. Understanding how chemokines bind to and activate CCR5 and related receptors is the first step to design new pharmaceutical drugs that can selectively activate processes in the immune system.”

CCR5 drug antagonists available today contribute already significantly to the treatment of AIDS. Others are in clinical trials with the aim to prevent AIDS transmission. CCR5 inhibitors also show first positive results in the treatment of metastatic tumours. The present study significantly enhances our understanding of the activation mechanism of chemokine receptors, many of which are involved in infectious diseases, auto-immunological disorders and cancer. It also provides the basis for the improvement of anti-HIV drugs and for the development of novel compounds that can influence the immune system in a highly specific way.

Text: Based on a media release by Biozentrum at University of Basel with additions from the Paul Scherrer Institute