biostudies-literatureYun JSHollings Cancer Center, Medical University of South CarolinaMinistry of Science ICT and Future PlanningNIBIB NIH HHSNational Institutes of HealthNational Research Foundation of KoreaNIGMS NIH HHS89-95https://www.ebi.ac.uk/biostudies/studies/S-EPMC6145842biostudies-literatureUnknown504(1)The decapping exoribonuclease DXO functions in pre-mRNA capping quality control, and shows multiple biochemical activities such as decapping, deNADding, pyrophosphohydrolase, and 5'-3' exoribonuclease activities. Previous studies revealed the molecular mechanisms of DXO based on the structures in complexes with a product, substrate mimic, cap analogue, and 3'-NADP⁺. Despite several reports on the substrate-specific reaction mechanism, the inhibitory mechanism of DXO remains elusive. Here, we demonstrate that adenosine 3', 5'-bisphosphate (pAp), a known inhibitor of the 5'-3' exoribonuclease Xrn1, inhibits the nuclease activity of DXO based on the results of structural and biochemical experiments. We determined the crystal structure of the DXO-pAp-Mg²⁺ complex at 1.8 ÅBiochemical and biophysical research communicationsMolecular mechanism for the inhibition of DXO by adenosine 3',5'-bisphosphate.PMC61458422016R1C1B2009691R35 GM118093GM118093P30 EB0099982013R1A1A1061391Kim SChang JHYun JSTong LChoi YJYoon JHSon YJfalseMolecular mechanism for the inhibition of DXO by adenosine 3',5'-bisphosphate.The decapping exoribonuclease DXO functions in pre-mRNA capping quality control, and shows multiple biochemical activities such as decapping, deNADding, pyrophosphohydrolase, and 5'-3' exoribonuclease activities. Previous studies revealed the molecular mechanisms of DXO based on the structures in complexes with a product, substrate mimic, cap analogue, and 3'-NADP⁺. Despite several reports on the substrate-specific reaction mechanism, the inhibitory mechanism of DXO remains elusive. Here, we demonstrate that adenosine 3', 5'-bisphosphate (pAp), a known inhibitor of the 5'-3' exoribonuclease Xrn1, inhibits the nuclease activity of DXO based on the results of structural and biochemical experiments. We determined the crystal structure of the DXO-pAp-Mg²⁺ complex at 1.8 Å2018-01-01T00:00:00Z2018 Sep2025-06-01T03:31:42.967Z2019-10-11T07:16:16ZS-EPMC61458423018094710.1016/j.bbrc.2018.08.135