The ins and outs of ligand binding to CCR2

Leiden Repository

The ins and outs of ligand binding to CCR2

Title: The ins and outs of ligand binding to CCR2
Author: Zweemer, Annelien Jacomina Maria
Publisher: Division of Medicinal Chemistry of the Leiden Academic Centre for Drug Research,, Faculty of Science, Leiden University
Issue Date: 2014-11-20
Keywords: G protein-coupled receptors
Allosteric modulation
Ligand binding kinetics
Biased signalling
Abstract: 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
Description: Promotor: A.P. IJzerman, Co-Promotor: L.H. Heitman
With summary in Dutch
Faculty: Faculteit der Wiskunde en Natuurwetenschappen
Citation: Zweemer, A.J.M., 2014, Doctoral thesis, Leiden University
Sponsor: PeproTech
Handle: http://hdl.handle.net/1887/29763
 

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application/pdf Chapter 1 General introduction 1.445Mb View/Open
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application/pdf Chapter 7 Conclusions and future perspectives 3.052Mb View/Open
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