Structural biology of chemokine receptors.
Chemokine receptors are G protein-coupled receptors that mediate migration and activation of leukocytes as an important part of a protective immune response to injury and infection. In addition, chemokine receptors are used by HIV-1 to infect CD4 positive cells. The structural bases of chemokine receptor recognition and signal transduction are currently being investigated. High-resolution X-ray diffraction and NMR spectroscopy of chemokines indicate that all these peptides exhibit a common folding pattern, in spite of its low degree of primary-sequence homology. Chemokines' functional motifs have been identified by mutagenesis studies, and a possible mechanism for receptor recognition and activation is proposed, but high-resolution structure data of chemokine receptors is not yet available. Studies with receptor chimeras have identified the putative extracellular domains as the major selectivity determinants. Single-amino acid substitutions in the extracellular domains produce profound changes in receptor specificity, suggesting that motifs in these domains operate as a restrictive barrier to a common activation motif. Similarly HIV-1 usage of chemokine receptors involve interaction of one or more extracellular domains of the receptor with conserved and variable domains on the viral envelope protein gp 120, indicating a highly complex interaction. Elucidating the structural requirements for receptor interaction with chemokines and with HIV-1 will provide important insights into understanding the mechanisms of chemokine recognition and receptor activation. In addition, this information can greatly facilitate the design of effective immunomodulatory and anti-HIV-1 therapeutic agents.
Rojo
D
D
Department of Physiology and Biophysics, University of Texas Medical Branch, Galveston 77555-0641, USA. drojo@email.utmb.edu
Suetomi
K
K
Navarro
J
J
D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D006678:HIV / Q000378:metabolism*; D006801:Humans; D011487:Protein Conformation; D019707:Receptors, Chemokine / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D015728:Receptors, HIV / Q000378:metabolism; D013329:Structure-Activity Relationship
D019707:Receptors, Chemokine; D015728:Receptors, HIV