Background: The interaction between HIV-1 gp120 and CCR5 N terminus is critical for R5-virus entry and affects CCR5 antagonists' activity. Knowledge of how different genetic signatures of gp120 V3 domain effect the strength of this interaction is limited.
Methods: HIV-1 coreceptor usage was assessed in 251 patients using enhanced-sensitivity Trofile assay and V3 sequencing plus tropism prediction by Geno2pheno algorithm. Bayesian partitional model and recursive model selection have been used to define V3 genetic determinants correlated with different coreceptor usage. Gp120 interaction with CCR5 N terminus was evaluated by docking-analysis/molecular-dynamic simulations starting from the model described previously.
Results: Selected V3 genetic determinants (beyond known aminoacidic positions) significantly correlate with CCR5- or CXCR4-usage, and modulate gp120 affinity for CCR5 N terminus. This is the case for N5Y and N7K, absent in CCR5-using viruses and present in 4.5% and 6% of CXCR4-using viruses, respectively, and A19V, occurring in 2.6% of CCR5-using viruses and 22.0% of CXCR4-using viruses (P=10(-2) to 10(-7)). Their presence determines a decreased affinity for CCR5 N terminus even stronger than that observed in the presence of the well-known mutation S11R (N5Y: -6.60 Kcal/mol; N7K: -5.40 Kcal/mol; A19V: -5.60 Kcal/mol; S11R: -6.70 Kcal/mol; WT: -6.90 Kcal/mol). N7K significantly increases the distance between V3 position 7 and sulphotyrosine at CCR5 position 14 (crucial for binding to gp120; from 4.22 Å to 8.30 Å), thus abrogating the interaction between these two important residues.
Conclusions: Key determinants for tropism within the V3 sequence, confirmed by structure- and by phenotypic-tropism, have been identified. This information can be used for a finer tuning of potential efficacy of CCR5-antagonists in clinical practice, and to provide molecular implications for design of new entry inhibitors.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.3851/IMP1862 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Chemokine Receptor N-Terminus Charge Dictates Reliance on Post-Translational Modifications for Effective Ligand Capture and Following Boosting by Defense Peptides.
Int J Mol Sci
October 2024
Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
The chemokine receptors CCR1 and CCR5 display overlapping expression patterns and ligand dependency. Here we find that ligand activation of CCR5, not CCR1, is dependent on N-terminal receptor O-glycosylation. Release from O-glycosylation dependency is obtained by increasing CCR5 N-terminus acidity to the level of CCR1.
View Article and Find Full Text PDFThermodynamic and molecular dynamic insights into how fusion influences peptide-tag recognition of an antibody.
Sci Rep
April 2024
Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan.
To understand the effect of protein fusion on the recognition of a peptide-tag by an antibody, we fused a CCR5-derived peptide-tag (pep1) to GFP and investigated its recognition by an anti-pep1 antibody, 4B08. First, to characterize the thermodynamic properties associated with the pep1-4B08 binding, isothermal titration calorimetry experiments were conducted. It was found that pep1 fused to the C-terminus of GFP (GFP-CT) enhanced the enthalpic gain by 2.
View Article and Find Full Text PDFChemokine N-terminal-derived peptides differentially regulate signaling by the receptors CCR1 and CCR5.
FEBS Lett
December 2023
Laboratory of Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Inflammatory chemokines are often elevated in disease settings, where the largest group of CC-chemokines are the macrophage inflammatory proteins (MIP), which are promiscuous for the receptors CCR1 and CCR5. MIP chemokines, such as CCL3 and CCL5 are processed at the N terminus, which influences signaling in a highly diverse manner. Here, we investigate the signaling capacity of peptides corresponding to truncated N termini.
View Article and Find Full Text PDFStructural Insights into Molecular Recognition and Receptor Activation in Chemokine-Chemokine Receptor Complexes.
J Med Chem
June 2023
Laboratoire d'Innovation Thérapeutique, UMR 7200 CNRS Université de Strasbourg, Faculté de Pharmacie, 67400 Illkirch-Graffenstaden, France.
The chemokine system is a key player in the functioning of the immune system and a sought-after target for drug candidates. The number of experimental structures of chemokines in complex with chemokine receptors has increased rapidly over the past few years, providing essential information for rational development of chemokine receptor ligands. Here, we perform a comparative analysis of all chemokine-chemokine receptor structures, with the aim of characterizing the molecular recognition processes and highlighting the relationships between chemokine structures and functional processes.
View Article and Find Full Text PDFIdentification of a conserved chemokine receptor motif that enables ligand discrimination.
Sci Signal
March 2022
Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
Extensive ligand-receptor promiscuity in the chemokine signaling system balances beneficial redundancy and specificity. However, this feature poses a major challenge to selectively modulate the system pharmacologically. Here, we identified a conserved cluster of three aromatic receptor residues that anchors the second extracellular loop (ECL2) to the top of receptor transmembrane helices (TM) 4 and 5 and enables recognition of both shared and specific characteristics of interacting chemokines.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!