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Structural and Biological Characterizations of Novel High-Affinity Fluorescent Probes with Overlapped and Distinctive Binding Regions on CXCR4

1
School of Life Sciences, Tsinghua University, Beijing 100084, China
2
Department of Medicine, Division of Infectious Diseases and Global Public Health, School of Medicine, University of California San Diego, La Jolla, CA 92037, USA
3
School of Life and Health Sciences, Chinese University of Hong Kong, Shenzhen 518172, China
*
Authors to whom correspondence should be addressed.
Molecules 2019, 24(16), 2928; https://doi.org/10.3390/molecules24162928
Received: 16 July 2019 / Revised: 9 August 2019 / Accepted: 10 August 2019 / Published: 13 August 2019
(This article belongs to the Section Chemical Biology)
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Abstract

CXC-type chemokine receptor 4 (CXCR4) is well known as a co-receptor for cellular entry and infection of human immunodeficiency virus type 1 (HIV-1). As an important member of the G protein-coupled receptor (GPCR) family, CXCR4 also mediates a variety of cellular processes and functions, such as cell chemotaxis, proliferation, and calcium signal transductions. Identification and characterization of molecular ligands or probes of CXCR4 have been an intensive area of investigations as such ligands or probes are of significant clinical values for the studies and treatments of HIV-1 infection and other human diseases mediated by the receptor. The crystal structures of CXCR4 in complex with different ligands have revealed two distinctive binding regions or subpockets. Thus, understanding the interactions of diverse ligands with these distinctive CXCR4 binding regions has become vital for elucidating the relationship between binding modes and biological mechanisms of ligand actions. Peptidic CVX15 is the only ligand that has been validated to bind one of these distinctive binding regions (or so called the major subpocket) of CXCR4. Therefore, in this study, we developed an efficient probe system including two high-affinity peptidic fluorescent probes, designated as FITC-CVX15 and FITC-DV1, with the aim of targeting distinctive CXCR4 subpockets. We conducted rational design and chemical characterization of the two CXCR4-specific probes and examined their application in biological experiments including competitive binding assays, flow cytometry analysis, and confocal imaging. Especially these two probes were applied in parallel CXCR4 competitive binding assays to detect and analyze potential binding modes of diverse CXCR4 ligands, together with molecular docking and simulations. Our results have indicated that these peptidic fluorescent probe systems provide novel ligand detecting tools, as well as present a new approach for analyzing distinctive binding modes of diverse CXCR4 ligands. View Full-Text
Keywords: CXC-type chemokine receptor 4 (CXCR4); HIV-1 infection; cancer metastasis; fluorescent peptidic probes; distinct subpockets; competitive ligand binding; molecular docking simulations CXC-type chemokine receptor 4 (CXCR4); HIV-1 infection; cancer metastasis; fluorescent peptidic probes; distinct subpockets; competitive ligand binding; molecular docking simulations
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Zhu, S.; Meng, Q.; Schooley, R.T.; An, J.; Xu, Y.; Huang, Z. Structural and Biological Characterizations of Novel High-Affinity Fluorescent Probes with Overlapped and Distinctive Binding Regions on CXCR4. Molecules 2019, 24, 2928.

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