title: Direct interaction between an allosteric agonist pepducin and the chemokine receptor CXCR4.
abstract: 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.
authors: Anchor Therapeutics, Cambridge, Massachusetts 02142, United States. jjanz@anchortx.com
authors: Jay M
authors: JM
authors: Janz
authors: Yong
authors: Y
authors: Ren
authors: Richard
authors: R
authors: Looby
authors: Manija A
authors: MA
authors: Kazmi
authors: Pallavi
authors: P
authors: Sachdev
authors: Amy
authors: A
authors: Grunbeck
authors: Lynn
authors: L
authors: Haggis
authors: Daniel
authors: D
authors: Chinnapen
authors: Amy Ying
authors: AY
authors: Lin
authors: Christoph
authors: C
authors: Seibert
authors: Thomas
authors: T
authors: McMurry
authors: Kenneth E
authors: KE
authors: Carlson
authors: Tom W
authors: TW
authors: Muir
authors: Stephen
authors: S
authors: Hunt
authors: Thomas P
authors: TP
authors: Sakmar
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000595:Amino Acid Sequence; D002460:Cell Line; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D055668:Photochemical Processes; D019718:Receptors, CXCR4 / Q000819:agonists* / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D010455:Peptides; D019718:Receptors, CXCR4