A Novel Synthetic Bivalent Ligand to Probe Chemokine Receptor CXCR4 Dimerization and Inhibit HIV-1 Entry.
Summary of "A Novel Synthetic Bivalent Ligand to Probe Chemokine Receptor CXCR4 Dimerization and Inhibit HIV-1 Entry."
The chemokine receptor CXCR4 is one of two principal coreceptors for HIV-1 entry into target cells. CXCR4 is known to form homodimers. We previously demonstrated that the amino (N)-terminus of viral macrophage protein (vMIP)-II is the major determinant for CXCR4 recognition, and that V1 peptide derived from the N-terminus of vMIP-II (1-21 residues) showed significant CXCR4 binding. Interestingly, an all-D-amino acid analog of V1 peptide, DV1 peptide, displayed even higher binding affinity and strong antiviral activity in inhibiting the replication of CXCR4-dependent HIV-1 strains. In the present 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 showed enhanced binding affinity and antiviral activity compared with 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-DV1 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 to further probe the functions of CXCR4 dimerization and to study CXCR4 heterodimerization with other receptors.
Affiliation
Journal Details
This article was published in the following journal.
Name: Biochemistry
ISSN: 1520-4995
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22897429
- DOI: http://dx.doi.org/10.1021/bi2016712
Medical and Biotech [MESH] Definitions
Chemokine Cxcl12
A CXC chemokine that is chemotactic for T-LYMPHOCYTES and MONOCYTES. It has specificity for CXCR4 RECEPTORS. Two isoforms of CXCL12 are produced by alternative mRNA splicing.
Receptor, Par-2
A G-protein-coupled, proteinase-activated receptor that is expressed in a variety of tissues including ENDOTHELIUM; LEUKOCYTES; and the GASTROINTESTINAL TRACT. The receptor is activated by TRYPSIN, which cleaves off the N-terminal peptide from the receptor. The new N-terminal peptide is a cryptic ligand for the receptor. The uncleaved receptor can also be activated by the N-terminal peptide present on the activated THROMBIN RECEPTOR and by small synthetic peptides that contain the unmasked N-terminal sequence.
Receptors, Cxcr4
CXCR receptors with specificity for CXCL12 CHEMOKINE. The receptors may play a role in HEMATOPOIESIS regulation and can also function as coreceptors for the HUMAN IMMUNODEFICIENCY VIRUS.
Immunologic Capping
An energy dependent process following the crosslinking of B CELL ANTIGEN RECEPTORS by multivalent ligands (bivalent anti-antibodies, LECTINS or ANTIGENS), on the B-cell surface. The crosslinked ligand-antigen receptor complexes collect in patches which flow to and aggregate at one pole of the cell to form a large mass - the cap. The caps may then be endocytosed or shed into the environment.
Chemokine Cxcl9
An INTEFERON-inducible CXC chemokine that is specific for the CXCR3 RECEPTOR.
PubMed Articles
The bivalent ligand approach has been utilized not only to study the underlying mechanism of G protein-coupled receptors dimerization and/or oligomerization, but also to enhance ligand affinity and/or...
In the absence of an experimentally determined binding mode for the cyclopentapeptide CXCR4 antagonists, we have rationally designed conformationally constrained analogs to further probe the small pep...
Recent evidence suggests that the chemokine axis of CXC chemokine ligand-12 and its receptor CXC chemokine receptor-4 (CXCL12/CXCR4) is highly expressed in gynecological tumors and the axis of CXC che...
Bivalent ligands of CXCR4 with rigid linkers for elucidation of the dimerization state in cells.
To date, challenges in the design of bivalent ligands for G protein-coupled receptors (GPCRs) have revealed difficulties stemming from lack of knowledge of the state of oligomerization of the GPCR. Th...
Recently, we identified extracellular ubiquitin as an endogenous CXC chemokine receptor (CXCR) 4 agonist. However, the receptor selectivity and molecular basis of the CXCR4 agonist activity of ubiquit...
Clinical Trials
Studies on the Significance of CXCR4-CXCL12 on Leukemic Cells Passing Through"Marrow-Blood Barrier"
Bone marrow consists of a complex hematopoietic cellular component.When the blood progenitor cells differentiate to mature cells, they will exit unassisted to peripheral blood. On the othe...
The specific aim of this study is to document the pharmacokinetics of DAT receptor occupancy of OROS and immediate release (IR) MPH using PET scanning with C-11 altropane as the ligand. We...
Safety Study of RTL1000 (Recombinant T Cell Receptor Ligand) in Subjects With Multiple Sclerosis
RTL1000 is a new agent that has not been previously tested in humans. It is thought that RTL may specifically control the abnormal immune response or attack against the insulation on the...
Trial Comparing Dual Probe Ultrasonic Lithotripsy to a Single Probe Ultrasonic Lithotripsy
Percutaneous nephrolithotomy (PNL), in conjunction with intracorporeal lithotripsy, allows for the rapid removal of any kidney stone regardless of size. Currently, the choice of intracorp...
Role of Chemokines and Proinflammatory Cytokines in Rheumatoid Synovial Pathological Changes
Rheumatoid arthritis is a common chronic destructive arthritis. Major pathology change in rheumatoid arthritis is synovium hyperplasia with bone and cartilage erosion. Infiltrates in synov...
