Role of 3D Structures in Understanding, Predicting, and Designing Molecular Interactions in the Chemokine Receptor Family

Abstract

The recently solved crystallographic structures of two chemokine receptors, CXCR4 and CCR5, provided valuable insights into the molecular mechanisms of chemokine receptor function and interaction with various ligands. However, they did not answer all of the questions. It remains an important role of the computational community to complement and expand the structural insights into areas where experimental structure determination efforts have not yet succeeded, such as studying receptor functional states or their complexes with small molecule and protein ligands of different classes. In this chapter, we provide an overview of pre- and post-structure efforts in understanding, predicting, and designing chemokine receptor interactions with small molecules and peptides, chemokines, and HIV gp120 proteins, as well as structure-guided insights regarding chemokine receptor dimerization and the impact of structures on rational molecular design initiatives. As an inherently challenging family of GPCRs, chemokine receptors may only reveal their secrets when tackled by the efficient symbiosis of computational approaches with experimental structure determination.