In Silico Identification of Cholesterol Binding Motifs in the Chemokine Receptor CCR3.

Evan Van Aalst,Jotham Koneri,Benjamin J Wylie

doi:10.3390/membranes11080570

Abstract

CC motif chemokine receptor 3 (CCR3) is a Class A G protein-coupled receptor (GPCR) mainly responsible for the cellular trafficking of eosinophils. As such, it plays key roles in inflammatory conditions, such as asthma and arthritis, and the metastasis of many deadly forms of cancer. However, little is known about how CCR3 functionally interacts with its bilayer environment. Here, we investigate cholesterol binding sites in silico through Coarse-Grained Molecular Dynamics (MD) and Pylipid analysis using an extensively validated homology model based on the crystal structure of CCR5. These simulations identified several cholesterol binding sites containing Cholesterol Recognition/Interaction Amino Acid Consensus motif (CRAC) and its inversion CARC motifs in CCR3. One such site, a CARC site in TM1, in conjunction with aliphatic residues in TM7, emerged as a candidate for future investigation based on the cholesterol residency time within the binding pocket. This site forms the core of a cholesterol binding site previously observed in computational studies of CCR2 and CCR5. Most importantly, these cholesterol binding sites are conserved in other chemokine receptors and may provide clues to cholesterol regulation mechanisms in this subfamily of Class A GPCRs.

Highlights

IntroductionG protein-coupled receptors (GPCRs) are integral membrane proteins comprising seven transmembrane alpha helices (TM), three extracellular (EC), and three intracellular (IC) loops involved in ligand-binding and G protein docking [1]
To investigate how cholesterol influences the behavior of chemokine receptor 3 (CCR3), we employed CoarseGrained Molecular Dynamics (CGMD)
We have generated and validated a homology model of CCR3 based on the CCR5 crystal structure

Summary

Introduction

G protein-coupled receptors (GPCRs) are integral membrane proteins comprising seven transmembrane alpha helices (TM), three extracellular (EC), and three intracellular (IC) loops involved in ligand-binding and G protein docking [1]. Chemokine receptors are a subfamily of Class A GCPRs expressed by immune cells that induce chemotaxis of the expressing cell through the binding of small protein agonists to the receptor’s orthosteric binding pocket [2]. The cognate receptor is defined based on the native ligand(s). CCR5 and CXCR4 are best understood given their known critical role in cellular human immunodeficiency virus (HIV) entry [4,5]. Cholesterol binding and dynamic dimerization sites were observed in both receptors from MD simulations [6]

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Discussion

Conclusion