Structural basis for CCR6 modulation by allosteric antagonists.

Autor: Wasilko DJ; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA., Gerstenberger BS; Medicine Design, Pfizer Inc., Cambridge, MA, USA., Farley KA; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA., Li W; Inflammation and Immunology Research, Pfizer Inc., Cambridge, MA, USA., Alley J; Inflammation and Immunology Research, Pfizer Inc., Cambridge, MA, USA., Schnute ME; Medicine Design, Pfizer Inc., Cambridge, MA, USA., Unwalla RJ; Medicine Design, Pfizer Inc., Cambridge, MA, USA., Victorino J; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA., Crouse KK; Inflammation and Immunology Research, Pfizer Inc., Cambridge, MA, USA., Ding R; Inflammation and Immunology Research, Pfizer Inc., Cambridge, MA, USA., Sahasrabudhe PV; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA., Vincent F; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA., Frisbie RK; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA., Dermenci A; Medicine Design, Pfizer Inc., Groton, CT, USA., Flick A; Medicine Design, Pfizer Inc., Groton, CT, USA., Choi C; Medicine Design, Pfizer Inc., Groton, CT, USA., Chinigo G; Medicine Design, Pfizer Inc., Groton, CT, USA., Mousseau JJ; Medicine Design, Pfizer Inc., Groton, CT, USA., Trujillo JI; Medicine Design, Pfizer Inc., Groton, CT, USA., Nuhant P; Medicine Design, Pfizer Inc., Cambridge, MA, USA., Mondal P; Medicine Design, Pfizer Inc., Groton, CT, USA., Lombardo V; Medicine Design, Pfizer Inc., Groton, CT, USA., Lamb D; Sosei Heptares, Steinmetz Building, Granta Park, Great Abington, Cambridge, UK.; Nxera Pharma UK Limited, Steinmetz Building, Granta Park, Great Abington, Cambridge, UK., Hogan BJ; Sosei Heptares, Steinmetz Building, Granta Park, Great Abington, Cambridge, UK.; Nxera Pharma UK Limited, Steinmetz Building, Granta Park, Great Abington, Cambridge, UK., Minhas GS; Sosei Heptares, Steinmetz Building, Granta Park, Great Abington, Cambridge, UK., Segala E; Sosei Heptares, Steinmetz Building, Granta Park, Great Abington, Cambridge, UK., Oswald C; Sosei Heptares, Steinmetz Building, Granta Park, Great Abington, Cambridge, UK., Windsor IW; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA., Han S; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA., Rappas M; Sosei Heptares, Steinmetz Building, Granta Park, Great Abington, Cambridge, UK.; Nxera Pharma UK Limited, Steinmetz Building, Granta Park, Great Abington, Cambridge, UK., Cooke RM; Sosei Heptares, Steinmetz Building, Granta Park, Great Abington, Cambridge, UK., Calabrese MF; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA., Berstein G; Inflammation and Immunology Research, Pfizer Inc., Cambridge, MA, USA., Thorarensen A; Medicine Design, Pfizer Inc., Cambridge, MA, USA., Wu H; Discovery Sciences, Medicine Design, Pfizer Inc., Groton, CT, USA. huixian.wu@pfizer.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 31; Vol. 15 (1), pp. 7574. Date of Electronic Publication: 2024 Aug 31.
DOI: 10.1038/s41467-024-52045-7
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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