Structural basis for CCR6 modulation by allosteric antagonists

David Jonathan Wasilko, Brian S. Gerstenberger, Kathleen A. Farley, Wei Li, Jennifer Alley, Mark E. Schnute, Ray J. Unwalla, Jorge Victorino, Kimberly K. Crouse, Ru Ding, Parag V. Sahasrabudhe, Fabien Vincent, Richard K. Frisbie, Alpay Dermenci, Andrew Flick, Chulho Choi, Gary Chinigo, James J. Mousseau, John I. Trujillo, Philippe Nuhant, Prolay Mondal, Vincent Lombardo, Daniel Lamb, Barbara J. Hogan, Gurdeep Singh Minhas, Elena Segala, Christine Oswald, Ian W. Windsor, Seungil Han, Mathieu Rappas, Robert M. Cooke, Matthew F. Calabrese, Gabriel Berstein, Atli Thorarensen and Huixian Wu ()
Additional contact information
David Jonathan Wasilko: Pfizer Inc.
Brian S. Gerstenberger: Pfizer Inc.
Kathleen A. Farley: Pfizer Inc.
Wei Li: Pfizer Inc.
Jennifer Alley: Pfizer Inc.
Mark E. Schnute: Pfizer Inc.
Ray J. Unwalla: Pfizer Inc.
Jorge Victorino: Pfizer Inc.
Kimberly K. Crouse: Pfizer Inc.
Ru Ding: Pfizer Inc.
Parag V. Sahasrabudhe: Pfizer Inc.
Fabien Vincent: Pfizer Inc.
Richard K. Frisbie: Pfizer Inc.
Alpay Dermenci: Pfizer Inc.
Andrew Flick: Pfizer Inc.
Chulho Choi: Pfizer Inc.
Gary Chinigo: Pfizer Inc.
James J. Mousseau: Pfizer Inc.
John I. Trujillo: Pfizer Inc.
Philippe Nuhant: Pfizer Inc.
Prolay Mondal: Pfizer Inc.
Vincent Lombardo: Pfizer Inc.
Daniel Lamb: Great Abington
Barbara J. Hogan: Great Abington
Gurdeep Singh Minhas: Great Abington
Elena Segala: Great Abington
Christine Oswald: Great Abington
Ian W. Windsor: Pfizer Inc.
Seungil Han: Pfizer Inc.
Mathieu Rappas: Great Abington
Robert M. Cooke: Great Abington
Matthew F. Calabrese: Pfizer Inc.
Gabriel Berstein: Pfizer Inc.
Atli Thorarensen: Pfizer Inc.
Huixian Wu: Pfizer Inc.

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-52045-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52045-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-52045-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().