Structural basis for CCR6 modulation by allosteric antagonists

Structural basis for CCR6 modulation by allosteric antagonists. Wasilko, D. J., Gerstenberger, B. S., Farley, K. A., Li, W., Alley, J., Schnute, M. E., Unwalla, R. J., Victorino, J., Crouse, K. K., Ding, R., Sahasrabudhe, P. V., Vincent, F., Frisbie, R. K., Dermenci, A., Flick, A., Choi, C., Chinigo, G., Mousseau, J. J., Trujillo, J. I., Nuhant, P., Mondal, P., Lombardo, V., Lamb, D., Hogan, B. J., Minhas, G. S., Segala, E., Oswald, C., Windsor, I. W., Han, S., Rappas, M., Cooke, R. M., Calabrese, M. F., Berstein, G., Thorarensen, A., & Wu, H. Nature Communications, 15(1):7574, August, 2024.

Paper doi abstract bibtex

The CC chemokine receptor 6 (CCR6) is a potential target for chronic inflammatory diseases. Previously, we reported an active CCR6 structure in complex with its cognate chemokine CCL20, revealing the molecular basis of CCR6 activation. Here, we present two inactive CCR6 structures in ternary complexes with different allosteric antagonists, CCR6/SQA1/OXM1 and CCR6/SQA1/OXM2. The oxomorpholine analogues, OXM1 and OXM2 are highly selective CCR6 antagonists which bind to an extracellular pocket and disrupt the receptor activation network. An energetically favoured U-shaped conformation in solution that resembles the bound form is observed for the active analogues. SQA1 is a squaramide derivative with close-in analogues reported as antagonists of chemokine receptors including CCR6. SQA1 binds to an intracellular pocket which overlaps with the G protein site, stabilizing a closed pocket that is a hallmark of inactive GPCRs. Minimal communication between the two allosteric pockets is observed, in contrast to the prevalent allosteric cooperativity model of GPCRs. This work highlights the versatility of GPCR antagonism by small molecules, complementing previous knowledge of CCR6 activation, and sheds light on drug discovery targeting CCR6.

@article{Wasilko2024,
  abstract = {The CC chemokine receptor 6 (CCR6) is a potential target for chronic inflammatory diseases. Previously, we reported an active CCR6 structure in complex with its cognate chemokine CCL20, revealing the molecular basis of CCR6 activation. Here, we present two inactive CCR6 structures in ternary complexes with different allosteric antagonists, CCR6/SQA1/OXM1 and CCR6/SQA1/OXM2. The oxomorpholine analogues, OXM1 and OXM2 are highly selective CCR6 antagonists which bind to an extracellular pocket and disrupt the receptor activation network. An energetically favoured U-shaped conformation in solution that resembles the bound form is observed for the active analogues. SQA1 is a squaramide derivative with close-in analogues reported as antagonists of chemokine receptors including CCR6. SQA1 binds to an intracellular pocket which overlaps with the G protein site, stabilizing a closed pocket that is a hallmark of inactive GPCRs. Minimal communication between the two allosteric pockets is observed, in contrast to the prevalent allosteric cooperativity model of GPCRs. This work highlights the versatility of GPCR antagonism by small molecules, complementing previous knowledge of CCR6 activation, and sheds light on drug discovery targeting CCR6.},
  added-at = {2024-09-23T16:26:35.000+0200},
  author = {Wasilko, David Jonathan and Gerstenberger, Brian S. and Farley, Kathleen A. and Li, Wei and Alley, Jennifer and Schnute, Mark E. and Unwalla, Ray J. and Victorino, Jorge and Crouse, Kimberly K. and Ding, Ru and Sahasrabudhe, Parag V. and Vincent, Fabien and Frisbie, Richard K. and Dermenci, Alpay and Flick, Andrew and Choi, Chulho and Chinigo, Gary and Mousseau, James J. and Trujillo, John I. and Nuhant, Philippe and Mondal, Prolay and Lombardo, Vincent and Lamb, Daniel and Hogan, Barbara J. and Minhas, Gurdeep Singh and Segala, Elena and Oswald, Christine and Windsor, Ian W. and Han, Seungil and Rappas, Mathieu and Cooke, Robert M. and Calabrese, Matthew F. and Berstein, Gabriel and Thorarensen, Atli and Wu, Huixian},
  biburl = {https://www.bibsonomy.org/bibtex/28c6bcc5568d55a117324fa95f8af4c04/cryoem_staff},
  day = 31,
  doi = {10.1038/s41467-024-52045-7},
  interhash = {7ea6f94c9bb8194e23b3933d27988879},
  intrahash = {8c6bcc5568d55a117324fa95f8af4c04},
  issn = {2041-1723},
  journal = {Nature Communications},
  keywords = {2024},
  month = aug,
  number = 1,
  pages = 7574,
  timestamp = {2024-09-23T16:26:35.000+0200},
  title = {Structural basis for CCR6 modulation by allosteric antagonists},
  url = {https://doi.org/10.1038/s41467-024-52045-7},
  volume = 15,
  year = 2024
}

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