The Biology of Leukocyte Chemoattractant receptors

Dr James Pease, Head of Group

Leukocytes (white blood cells) need to be able to move rapidly within the body to maintain an anti-microbial response to invading organisms such as bacteria. Their movement is coordinated by proteins on the leukocyte cell surface known as chemoattractant receptors. These have been likened to a ‘sat nav’ device and pick up chemical signals from molecules known as chemoattractants. The chemical signals instruct the leukocyte to move in the direction of the signal. Once chemoattractants have recruited leukocytes to the tissues, the leukocytes typically destroy the invader. This is a highly desirable process.

However, in many clinically important diseases including asthma, artherosclerosis (hardening of the arteries) and rheumatoid arthritis, the inadvertent or excessive production of chemoattractants results in leukocyte recruitment and a process known as inflammation. If unchecked, the inflammation can result in severe tissue damage with life- threatening consequences.

Chemoattractant receptors belong to a large family of proteins known as G protein-coupled receptors (GPCRs). My group has focused upon the chemokine family of GPCRs and our research is aimed at appreciating how these molecules function at the molecular level.

Members of our section are used to depict our current understanding of how a chemokine receptor is activated. The receptor is shown in blue with seven transmembrane domains which projects into both the extracellular (lawn) and intracellular (pavement) spaces. A chemokine (yellow) is shown binding to the extracellular regions of the receptor and activating the receptor by insertion of its amino-terminus into the intrahelical pocket.

If specific drugs or “blockers” can be developed which stop the chemoattractant receptor from relaying a signal, then these may have considerable therapeutic potential (1). We have deduced how a number of prototype drugs block chemokine receptor function by binding in an internal pocket (2). One such example is shown in the interactive Jmol applet on the right. Clicking on the model will allow you to explore it further.

[embedded jmol file here]

The drug UCB35625 (magenta) was found to interacts with the residues Y41, Y113 and E287 (shown as sticks) of the receptor helices, blocking access to interhelical residues thought to be involved in receptor activation. A schematic representation is shown inset. Molecular modelling was kindly performed by Dr Paola da Fonseca.

On-going projects within my group are concerned with a variety of chemoattractant receptors involved in inflammatory processes, both chemokine and non-chemokine receptors. We are interested in all aspects of receptor biology, notably the regulation of receptor gene expression and receptor function and also the trafficking of receptors to and from the plasma membrane (3).

References

1. Pease JE; Horuk R. ( 2009).  Chemokine receptor antagonists: Part 1. EXPERT OPIN THER PAT. 19:39-58. DOI.; Chemokine receptor antagonists: part 2. EXPERT OPIN THER PAT. 19:199-221. DOI.
2. Wise EL; Duchesnes C; da Fonseca PCA; Allen RA; Williams TJ; Pease JE. (21 Sep 2007). Small molecule receptor agonists and antagonists of CCR3 provide insight into mechanisms of chemokine receptor activation. J BIOL CHEM. 282:27935-27943. DOI.
3. Meiser A; Mueller A; Wise EL; McDonagh EM; Petit SJ; Saran N; Clark PC; Williams TJ; et al. (15 May 2008). The chemokine receptor CXCR3 is degraded following internalization and is replenished at the cell surface by de novo synthesis of receptor. J IMMUNOL. 180:6713-6724.