7P8P

Crystal structure of Fhit covalently bound to a nucleotide

Summary for 7P8P

• Entry DOI: 10.2210/pdb7p8p/pdb
• Descriptor: Bis(5'-adenosyl)-triphosphatase, [(2~{R},3~{S},4~{R},5~{R})-5-[6-(ethylamino)purin-9-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methyl dihydrogen phosphate, SODIUM ION, ... (5 entities in total)
• Functional Keywords: fhit, ap3a, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 77499.76

Authors

Herzog, D.,Missun, M.,Diederichs, K.,Marx, A. (deposition date: 2021-07-23, release date: 2022-06-01, Last modification date: 2024-11-06)

Primary citation

Herzog, D.,Jansen, J.,Missun, M.,Diederichs, K.,Stengel, F.,Marx, A.
Chemical Proteomics of the Tumor Suppressor Fhit Covalently Bound to the Cofactor Ap 3 A Elucidates Its Inhibitory Action on Translation.
J.Am.Chem.Soc., 144:8613-8623, 2022

PubMed Abstract: The tumor suppressor protein (Fhit) is known to be associated with genomic instability and apoptosis. The tumor-suppressive function of Fhit depends on the interaction with the alarmone diadenosine triphosphate (ApA), a noncanonical nucleotide whose concentration increases upon cellular stress. How the Fhit-ApA complex exerts its signaling function is unknown. Here, guided by a chemical proteomics approach employing a synthetic stable Fhit-ApA complex, we found that the Fhit-ApA complex, but not Fhit or ApA alone, impedes translation. Our findings provide a mechanistic model in which Fhit translocates from the nucleolus into the cytosol upon stress to form an Fhit-ApA complex. The Fhit-ApA complex impedes translation both and , resulting in reduced cell viability. Overall, our findings provide a mechanistic model by which the tumor suppressor Fhit collaborates with the alarmone ApA to regulate cellular proliferation.

PubMed: 35522782
DOI: 10.1021/jacs.2c00815

Experimental method

X-RAY DIFFRACTION (2.34 Å)