CCR5 mutations distinguish N-terminal modifications of RANTES (CCL5) with agonist versus antagonist activity.
CCR5 is the major HIV-1 entry coreceptor. RANTES/CCL5 analogs are more potent inhibitors of infection than native chemokines; one class activates and internalizes CCR5, one neither activates nor internalizes, and a third partially internalizes without activation. Here we show that mutations in CCR5 transmembrane domains differentially impact the activity of these three inhibitor classes, suggesting that the transmembrane region of CCR5, a key interaction site for inhibitors, is a sensitive molecular switch, modulating receptor activity.
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
Won-Tak
WT
Choi
Rebecca
R
Nedellec
Mia
M
Coetzer
Philippe
P
Colin
Bernard
B
Lagane
Robin E
RE
Offord
Oliver
O
Hartley
Donald E
DE
Mosier
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology; D002460:Cell Line; D018946:Chemokine CCL5 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D017434:Protein Structure, Tertiary; D019713:Receptors, CCR5 / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction; D053586:Virus Internalization / Q000187:drug effects
D019380:Anti-HIV Agents; C483024:CCL5 protein, human; D018946:Chemokine CCL5; D019713:Receptors, CCR5