Membrane proteins such as G protein-coupled receptors (GPCRs) are involved in awide range of physiological and pathological cellular processes. Binding of extracellular signals to GPCRs, including hormones, neurotransmitters, peptides and proteins, can activate intracellular signaling cascades via G protein interaction. Chemokine receptors are key GPCRs implicated in cancers, immune responses, cell migration and inflammation. Specifically, the CCR5 and CXCR4 chemokine receptors serve as important therapeutic targets against Human Immunodeficiency virus (HIV) entry into human cells. Maraviroc and Vicriviroc, two clinically used HIV entry inhibitors, are antagonists of the CCR5 receptor. These drugs block HIV entry, but ultimately resistance develops, due to emergence of viruses that can utilize the CXCR4 co-receptor. Unfortunately, development of chemokine receptor antagonists as selective drugs of HIV infection has been greatly hindered as their target orthosteric site is conserved among different receptor subtypes. Accordingly, it is important to understand the structural dynamics of these receptors to develop more effective therapeutics. In this chapter, we describe the latest advances in studies of these two key chemokine receptors with respect to their structures, dynamics and function.
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