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

doi:10.1021/ja206661w

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

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62 Scopus citations

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.

Original language	English (US)
Pages (from-to)	15878-15881
Number of pages	4
Journal	Journal of the American Chemical Society
Volume	133
Issue number	40
DOIs	https://doi.org/10.1021/ja206661w
State	Published - Oct 12 2011

All Science Journal Classification (ASJC) codes

Catalysis
Chemistry(all)
Biochemistry
Colloid and Surface Chemistry

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10.1021/ja206661w

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Janz, J. M., Ren, Y., Looby, R., Kazmi, M. A., Sachdev, P., Grunbeck, A., Haggis, L., Chinnapen, D., Lin, A. Y., Seibert, C., McMurry, T., Carlson, K. E., Muir, T. W., Hunt, S., & Sakmar, T. P. (2011). Direct interaction between an allosteric agonist pepducin and the chemokine receptor CXCR4. Journal of the American Chemical Society, 133(40), 15878-15881. https://doi.org/10.1021/ja206661w

@article{f65805d8793f464a9079907e6a8437aa,

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.",

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

year = "2011",

month = oct,

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doi = "10.1021/ja206661w",

language = "English (US)",

volume = "133",

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Janz, JM, Ren, Y, Looby, R, Kazmi, MA, Sachdev, P, Grunbeck, A, Haggis, L, Chinnapen, D, Lin, AY, Seibert, C, McMurry, T, Carlson, KE, Muir, TW, Hunt, S & Sakmar, TP 2011, 'Direct interaction between an allosteric agonist pepducin and the chemokine receptor CXCR4', Journal of the American Chemical Society, vol. 133, no. 40, pp. 15878-15881. https://doi.org/10.1021/ja206661w

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T1 - Direct interaction between an allosteric agonist pepducin and the chemokine receptor CXCR4

AU - Janz, Jay M.

AU - Ren, Yong

AU - Looby, Richard

AU - Kazmi, Manija A.

AU - Sachdev, Pallavi

AU - Grunbeck, Amy

AU - Haggis, Lynn

AU - Chinnapen, Daniel

AU - Lin, Amy Ying

AU - Seibert, Christoph

AU - McMurry, Thomas

AU - Carlson, Kenneth E.

AU - Muir, Tom W.

AU - Hunt, Stephen

AU - Sakmar, Thomas P.

PY - 2011/10/12

Y1 - 2011/10/12

N2 - 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.

AB - 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.

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ER -

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

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