Dissertation

The ins and outs of ligand binding to CCR2

Promotor: Prof.dr. A. P. IJzerman, Co-Promotor: Dr. L.H. Heitman

Author

A.J.M. Zweemer

Date

20 November 2014

Links

Thesis in Leiden Repository

This thesis provides novel insights in the molecular mechanism of action of antagonists for the chemokine receptor CCR2. CCR2 belongs to the protein family of G protein-coupled receptors (GPCRs). It is involved in several inflammatory diseases and therefore many small molecule antagonists targeting this receptor have been developed over the years. Unfortunately all clinical candidates tested so far appeared to lack efficacy in man, which stresses the need for a better understanding of their mechanism of action. This thesis revealed three separate binding pockets throughout the transmembrane receptor domain via which CCR2 can be pharmacologically modulated. Different routes towards insurmountable antagonism of CCR2 were described, either via noncompetitive or via long residence time antagonists. These results may allow a more rational design of future antagonists, and are equally important to understand the outcomes of studies with existing CCR2 antagonists. In concert with the currently expanding insight in the structure and signalling capacities of GPCRs, the data presented in this thesis allow to better fine-tune the pharmacological modulation of the chemokine receptor CCR2, and GPCRs in general.

• allosteric modulation
• biased signalling
• g protein-coupled receptors
• ligand binding kinetics