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

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Chemokines

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 14))

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.

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Abbreviations

3D:

Three-dimensional

AUC:

Area under curve

BiFC:

Biomolecular fluorescence complementation

BRET:

Bioluminescence resonance energy transfer

CCR5:

CC chemokine receptor 5

CXCR4:

CXC chemokine receptor 4

ECL:

Extracellular loop

FRET:

Fluorescence resonance energy transfer

GPCR:

G-protein-coupled receptor

HIV:

Human immunodeficiency virus

NMR:

Nuclear magnetic resonance

PDB:

Protein data bank

ROC:

Receiver operating characteristic

SDF-1:

Stromal cell derived factor 1

TM:

Transmembrane

VLS:

Virtual ligand screening

WT:

Wild type

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Acknowledgements

Authors thank Dr. Seva Katritch, The Scripps Research Institute, for valuable discussions and insights, and Eugene Raush, Molsoft LLC, for the help with molecular graphics. This work is partially funded by National Institutes of Health grants R01 GM071872, U01 GM094612, U54 GM094618.

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  1. UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA

    Irina Kufareva, Ruben Abagyan & Tracy M. Handel

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  1. Irina Kufareva
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  2. Ruben Abagyan
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  3. Tracy M. Handel
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Correspondence to Irina Kufareva .

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  1. Dept. of Chemistry and Pharmacy, Friedrich Alexander University, Erlangen, Germany

    Nuska Tschammer

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Kufareva, I., Abagyan, R., Handel, T.M. (2014). Role of 3D Structures in Understanding, Predicting, and Designing Molecular Interactions in the Chemokine Receptor Family. In: Tschammer, N. (eds) Chemokines. Topics in Medicinal Chemistry, vol 14. Springer, Cham. https://doi.org/10.1007/7355_2014_77

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