Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
27
pubmed:dateCreated
2002-7-1
pubmed:abstractText
CXCR4 is a G protein-coupled receptor for stromal-derived factor 1 (SDF-1) that plays a critical role in leukocyte trafficking, metastasis of mammary carcinoma, and human immunodeficiency virus type-1 infection. To elucidate the mechanism for CXCR4 activation, a constitutively active mutant (CAM) was derived by coupling the receptor to the pheromone response pathway in yeast. Conversion of Asn-119 to Ser or Ala, but not Asp or Lys, conferred autonomous CXCR4 signaling in yeast and mammalian cells. SDF-1 induced signaling in variants with substitution of Asn-119 to Ser, Ala, or Asp, but not Lys. These variants had similar cell surface expression and binding affinity for SDF-1. CXCR4-CAMs were constitutively phosphorylated and present in cytosolic inclusions. Analysis of antagonists revealed that exposure to AMD3100 or ALX40-4C induced G protein activation by CXCR4 wild type, which was greater in the CAM, whereas T140 decreased autonomous signaling. The affinity of AMD3100 and ALX40-4C binding to CAMs was less than to wild type, providing evidence of a conformational shift. These results illustrate the importance of transmembrane helix 3 in CXCR4 signaling. Insight into the mechanism for CXCR4 antagonists will allow for the development of a new generation of agents that lack partial agonist activity that may induce toxicities, as observed for AMD3100.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
5
pubmed:volume
277
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
24515-21
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:11923301-Amino Acid Substitution, pubmed-meshheading:11923301-Animals, pubmed-meshheading:11923301-Anti-HIV Agents, pubmed-meshheading:11923301-CHO Cells, pubmed-meshheading:11923301-Cricetinae, pubmed-meshheading:11923301-GTP-Binding Proteins, pubmed-meshheading:11923301-Genes, Reporter, pubmed-meshheading:11923301-Genetic Variation, pubmed-meshheading:11923301-Heterocyclic Compounds, pubmed-meshheading:11923301-Humans, pubmed-meshheading:11923301-Oligopeptides, pubmed-meshheading:11923301-Open Reading Frames, pubmed-meshheading:11923301-Point Mutation, pubmed-meshheading:11923301-Protein Conformation, pubmed-meshheading:11923301-Receptors, CXCR4, pubmed-meshheading:11923301-Recombinant Proteins, pubmed-meshheading:11923301-Saccharomyces cerevisiae, pubmed-meshheading:11923301-Signal Transduction, pubmed-meshheading:11923301-Transfection
pubmed:year
2002
pubmed:articleTitle
A point mutation that confers constitutive activity to CXCR4 reveals that T140 is an inverse agonist and that AMD3100 and ALX40-4C are weak partial agonists.
pubmed:affiliation
Henry Vogt Cancer Research Institute, University of Louisville, Louisville, Kentucky 40202, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't