Direct interaction between an allosteric agonist pepducin and the chemokine receptor CXCR4

Jay M. Janz, Yong Ren, Richard Looby, Manija A. Kazmi, Pallavi Sachdev, Amy Grunbeck, Lynn Haggis, Daniel Chinnapen, Amy Ying Lin, Christoph Seibert, Thomas McMurry, Kenneth E. Carlson, Tom W. Muir, Stephen Hunt, Thomas P. Sakmar

Research output: Contribution to journalArticlepeer-review

63 Scopus citations


Cell surface heptahelical G protein-coupled receptors (GPCRs) mediate critical cellular signaling pathways and are important pharmaceutical drug targets.(1)In addition to traditional small-molecule approaches, lipopeptide-based GPCR-derived pepducins have emerged as a new class of pharmaceutical agents.(2, 3)To better understand how pepducins interact with targeted receptors, we developed a cell-based photo-cross-linking approach to study the interaction between the pepducin agonist ATI-2341 and its target receptor, chemokine C-X-C-type receptor 4 (CXCR4). A pepducin analogue, ATI-2766, formed a specific UV-light-dependent cross-link to CXCR4 and to mutants with truncations of the N-terminus, the known chemokine docking site. These results demonstrate that CXCR4 is the direct binding target of ATI-2341 and suggest a new mechanism for allosteric modulation of GPCR activity. Adaptation and application of our findings should prove useful in further understanding pepducin modulation of GPCRs as well as enable new experimental approaches to better understand GPCR signal transduction.

Original languageEnglish (US)
Pages (from-to)15878-15881
Number of pages4
JournalJournal of the American Chemical Society
Issue number40
StatePublished - Oct 12 2011

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • Biochemistry
  • Catalysis
  • Colloid and Surface Chemistry


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