Structural basis for CCR6 modulation by allosteric antagonists

Area of Science:

• Structural biology
• Pharmacology
• Immunology

Background:

• CC chemokine receptor 6 (CCR6) is a key target for chronic inflammatory diseases.
• Previous studies elucidated the active CCR6 structure bound to CCL20, detailing receptor activation mechanisms.

Purpose of the Study:

• To present inactive CCR6 structures in complex with novel allosteric antagonists.
• To elucidate the molecular basis of CCR6 antagonism by small molecules.
• To explore the allosteric communication within CCR6 upon antagonist binding.

Main Methods:

• X-ray crystallography was used to determine the ternary structures of CCR6 with antagonists SQA1/OXM1 and SQA1/OXM2.
• Biophysical techniques were employed to characterize antagonist binding and conformational states.
• Computational modeling was used to assess conformational preferences in solution.

Main Results:

• Two distinct inactive CCR6 structures were solved, complexed with oxomorpholine (OXM1, OXM2) and squaramide (SQA1) derivatives.
• Antagonists bind to separate extracellular and intracellular pockets, disrupting the receptor activation network.
• Minimal allosteric communication was observed between the two antagonist-binding sites, challenging conventional GPCR cooperativity models.

Conclusions:

• Small molecules can effectively antagonize CCR6 by stabilizing inactive conformations through distinct binding pockets.
• The findings provide structural insights into CCR6 allosteric antagonism, complementing knowledge of receptor activation.
• This work supports the development of novel therapeutics targeting CCR6 for inflammatory conditions.