The adenosine subfamily G protein-coupled receptors A_(2A)R and A_(2B)R have been identified as promising cancer immunotherapy candidates.One of the A_(2A)R/A_(2B)R dual antagonists,AB928,has progressed to a phaseⅡcl...The adenosine subfamily G protein-coupled receptors A_(2A)R and A_(2B)R have been identified as promising cancer immunotherapy candidates.One of the A_(2A)R/A_(2B)R dual antagonists,AB928,has progressed to a phaseⅡclinical trial to treat rectal cancer.However,the precise mechanism underlying its dual-antagonistic properties remains elusive.Herein,we report crystal structures of the A_(2A)R complexed with AB928 and a selective A_(2A)R antagonist 2-118.The structures revealed a common binding mode on A_(2A)R,wherein the ligands established extensive interactions with residues from the orthosteric and secondary pockets.In contrast,the cAMP assay and A_(2A)R and A_(2B)R molecular dynamics simulations indicated that the ligands adopted distinct binding modes on A_(2B)R.Detailed analysis of their chemical structures suggested that AB928 readily adapted to the A_(2B)R pocket,while 2-118 did not due to intrinsic differences.This disparity potentially accounted for the difference in inhibitory efficacy between A_(2B)R and A_(2A)R.This study serves as a valuable structural template for the future development of selective or dual inhibitors targeting A_(2A)R/A_(2B)R for cancer therapy.展开更多
基金supported by the National Key Research and Development Program of China(2018YFA0507001)the Basic Research Program of Science and Technology Commission of Shanghai Municipality(21JC1402400)+1 种基金the National Natural Science Foundation of China(32171215,81972828,82172644,82273857 and 81830083)the National Key Scientific Infrastructure for Translational Medicine(Shanghai)(TMSK-2021-120)。
文摘The adenosine subfamily G protein-coupled receptors A_(2A)R and A_(2B)R have been identified as promising cancer immunotherapy candidates.One of the A_(2A)R/A_(2B)R dual antagonists,AB928,has progressed to a phaseⅡclinical trial to treat rectal cancer.However,the precise mechanism underlying its dual-antagonistic properties remains elusive.Herein,we report crystal structures of the A_(2A)R complexed with AB928 and a selective A_(2A)R antagonist 2-118.The structures revealed a common binding mode on A_(2A)R,wherein the ligands established extensive interactions with residues from the orthosteric and secondary pockets.In contrast,the cAMP assay and A_(2A)R and A_(2B)R molecular dynamics simulations indicated that the ligands adopted distinct binding modes on A_(2B)R.Detailed analysis of their chemical structures suggested that AB928 readily adapted to the A_(2B)R pocket,while 2-118 did not due to intrinsic differences.This disparity potentially accounted for the difference in inhibitory efficacy between A_(2B)R and A_(2A)R.This study serves as a valuable structural template for the future development of selective or dual inhibitors targeting A_(2A)R/A_(2B)R for cancer therapy.
