Direct interaction between an allosteric agonist pepducin and the chemokine receptor CXCR4
| Autor: | Daniel J.-F. Chinnapen, Stephen W. Hunt, Manija A. Kazmi, Richard J. Looby, Yong Ren, Kenneth E. Carlson, Thomas P. Sakmar, Amy Ying Lin, Tom W. Muir, Lynn Haggis, Jay M. Janz, Christoph Seibert, Thomas J. McMurry, Amy Grunbeck, Pallavi Sachdev |
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| Rok vydání: | 2011 |
| Předmět: |
Agonist
Models Molecular Cell signaling Receptors CXCR4 medicine.drug_class Ultraviolet Rays Allosteric regulation Molecular Sequence Data Biochemistry Catalysis Cell Line Chemokine receptor Colloid and Surface Chemistry Allosteric Regulation medicine Humans Amino Acid Sequence Pepducin Receptor G protein-coupled receptor Chemistry General Chemistry Photochemical Processes Cell biology Docking (molecular) Peptides |
| Zdroj: | Journal of the American Chemical Society. 133(40) |
| ISSN: | 1520-5126 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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