Research Projects
Blocking The Interaction Between the HIV Envelope Protein and the Chemokine Receptors CCR5 and CXCR4
This project aims to determine the structure of the CCR5 chemokine receptor structure at its ligand binding site and its interaction with agonist and antagonist molecules. CCR5 is the major co-receptor required for infection by primary isolates of HIV (the M-tropic/R5 strains predominantly transmitted between people). The goals of the project are to: (1) Synthesize photo-activatable analogs of non-peptide antagonists that block HIV infection. (2) Photo-crosslink bioactive analogs to CCR5, and locate crosslinking sites using mass spectrometry (LC/MS/MS) to map the antagonist binding pocket in CCR5. (3) Map the structure of the HIV/chemokine binding pocket of CCR5 by scanning photoactivatable amino acid analogs over chemokine peptide agonist sequences, photocrosslinking the bioactive analogs to CCR5, and using MS to determine residues lining the binding sites. (4) Analyze the conformation of CCR5 with bound antagonist vs. agonist by mapping discontinuous epitopes of antibodies that discriminate between these conformations of CCR5, using random peptide libraries displayed on phage. (5) Determine the structures of these peptide epitopes bound to the antibodies using x-ray crystallography. The ultimate goal is to provide a foundation for more effective structure-based design of HIV entry inhibitors. A similar approach is being used with antagonists of the other main HIV co-receptor CXCR4.
Personnel:
Martin Teintze
Keywords:
Biochemistry
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