biostudies-literatureTian HNSF (NSF)DOD | ARPA | Defense Sciences Office, DARPA (DSO)HHS | NIH | National Institute on Aging (NIA)HHS | NIH | National Institute of General Medical Sciences (NIGMS)e2519924122https://www.ebi.ac.uk/biostudies/studies/S-EPMC12745708biostudies-literatureUnknown122(51)Small-molecule sensing in plants is dominated by chemical-induced dimerization modules. In the abscisic acid (ABA) system, allosteric receptors recruit phosphatase effectors and achieve nM in vivo responses from µM receptor-ligand interactions. This sensitivity amplification could enable ABA receptors to serve as generic scaffolds for designing small-molecule sensors. To test this, we screened collections of mutant ABA-receptors against 2,726 drugs and other ligands and identified 553 sensors for 6.6% of these ligands. The mutational patterns indicate strong selection for ligand-specific binding pockets. We used these data to develop a sensor design pipeline and isolated sensors for multiple plant natural products, 2,4,6-trinitrotoluene (TNT), and "forever" per- and polyfluoroalkyl substances (PFAS). Thus, the ABA sensor system enables design and isolation of small-molecule sensors with broad chemical scope and antibody-like simplicity.Proceedings of the National Academy of Sciences of the United States of AmericaUnusually broad-spectrum small-molecule sensing using a single protein scaffold.PMC12745708CERES-D24AC00011922642U19AG023122MRI-221570521282872128016R01-GM151616Girke TSeder NWhitehead TATian HDavis ZISwift SDLenert-Mondou CBeltran JCutler SRWheeldon IGeorge WfalseUnusually broad-spectrum small-molecule sensing using a single protein scaffold.Small-molecule sensing in plants is dominated by chemical-induced dimerization modules. In the abscisic acid (ABA) system, allosteric receptors recruit phosphatase effectors and achieve nM in vivo responses from µM receptor-ligand interactions. This sensitivity amplification could enable ABA receptors to serve as generic scaffolds for designing small-molecule sensors. To test this, we screened collections of mutant ABA-receptors against 2,726 drugs and other ligands and identified 553 sensors for 6.6% of these ligands. The mutational patterns indicate strong selection for ligand-specific binding pockets. We used these data to develop a sensor design pipeline and isolated sensors for multiple plant natural products, 2,4,6-trinitrotoluene (TNT), and "forever" per- and polyfluoroalkyl substances (PFAS). Thus, the ABA sensor system enables design and isolation of small-molecule sensors with broad chemical scope and antibody-like simplicity.2025-01-01T00:00:00Z2025 Dec2026-06-08T05:42:00.465Z2026-06-08T03:09:22.621ZS-EPMC127457084139712510.1073/pnas.2519924122