Structural determinants of CCR5 recognition and HIV-1 blockade in RANTES.
Certain chemokines act as natural antagonists of human immunodeficiency virus (HIV) by blocking key viral coreceptors, such as CCR5 and CXCR4, on the surface of susceptible cells. Elucidating the structural determinants of the receptor-binding and HIV-inhibitory functions of these chemokines is essential for the rational design of derivative molecules of therapeutic value. Here, we identify the structural determinants of CCR5 recognition and antiviral activity of the CC chemokine RANTES, showing that critical residues form a solvent-exposed hydrophobic patch on the surface of the molecule. Moreover, we demonstrate that the biological function is critically dependent on dimerization, resulting in the exposure of a large ( approximately 180 A2), continuous hydrophobic surface. Relevant to the development of novel therapeutic approaches, we designed a retroinverted RANTES peptide mimetic that maintained both HIV- and chemotaxis-antagonistic functions.
Nardese
V
V
Unit ofHuman Virology, DIBIT, San Raffaele Scientific Institute, 20132 Milan, Italy.
Longhi
R
R
Polo
S
S
Sironi
F
F
Arcelloni
C
C
Paroni
R
R
DeSantis
C
C
Sarmientos
P
P
Rizzi
M
M
Bolognesi
M
M
Pavone
V
V
Lusso
P
P
D000409:Alanine / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D018946:Chemokine CCL5 / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D018920:Coculture Techniques; D019281:Dimerization; D015195:Drug Design; D015726:Giant Cells / Q000187:drug effects / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008958:Models, Molecular; D018716:Molecular Mimicry; D016296:Mutagenesis / Q000235:genetics; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D019713:Receptors, CCR5 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D010455:Peptides; D019713:Receptors, CCR5; D011994:Recombinant Proteins; D000409:Alanine