A Novel Synthetic Bivalent Ligand To Probe Chemokine Receptor CXCR4 Dimerization and Inhibit HIV-1 Entry

详细信息    查看全文

• 作者：Won-Tak Choi ; Santhosh Kumar ; Navid Madani ; Xiaofeng Han ; Shaomin Tian ; Chang-Zhi Dong ; Dongxiang Liu ; Srinivas Duggineni ; Jian Yuan ; Joseph G. Sodroski ; Ziwei Huang ; Jing An
• 刊名：Biochemistry
• 出版年：2012
• 出版时间：September 11, 2012
• 年：2012
• 卷：51
• 期：36
• 页码：7078-7086
• 全文大小：401K
• 年卷期：v.51,no.36(September 11, 2012)
• ISSN：1520-4995

文摘

Chemokine receptor CXCR4 is one of two principal coreceptors for the entry of HIV-1 into target cells. CXCR4 is known to form homodimers. We previously demonstrated that the amino terminus of viral macrophage protein II (vMIP-II) is the major determinant for CXCR4 recognition, and that V1 peptide derived from the N-terminus of vMIP-II (1鈥?1 residues) showed significant CXCR4 binding. Interestingly, an all-d-amino acid analogue of V1 peptide, DV1 peptide, displayed an even higher binding affinity and strong antiviral activity in inhibiting the replication of CXCR4-dependent HIV-1 strains. In this study, we synthetically linked two DV1 peptides with the formation of a disulfide bond between the two cysteine residues present in the peptide sequence to generate a dimeric molecule potentially capable of interacting with two CXCR4 receptors. DV1 dimer exhibited enhanced binding affinity and antiviral activity compared with those of DV1 monomer. Ligand binding site mapping experiments showed that DV1 dimer overlaps with HIV-1 gp120 on CXCR4 binding sites, including several transmembrane (TM) residues located close to the extracellular side and the N-terminus of CXCR4. This finding was supported by the molecular modeling of CXCR4 dimer鈥揇V1 dimer interaction based on the crystal structure of CXCR4, which showed that DV1 dimer is capable of interacting with the CXCR4 dimeric structure by allowing the N-terminus of each DV1 monomer to reach into the binding pocket of CXCR4 monomer. The development of this bivalent ligand provides a tool for further probing the functions of CXCR4 dimerization and studying CXCR4 heterodimerization with other receptors.