8FIL

Zinc-free APOBEC3A (inactive E72A mutant) in complex with TTC-hairpin DNA substrate

Summary for 8FIL

• Entry DOI: 10.2210/pdb8fil/pdb
• Descriptor: DNA dC->dU-editing enzyme APOBEC-3A, DNA (5'-D(*TP*GP*CP*GP*CP*TP*TP*CP*GP*CP*GP*CP*T)-3'), INOSITOL HEXAKISPHOSPHATE, ... (5 entities in total)
• Functional Keywords: apobec, apobec3a, a3a, apobec3a e72a mutant, cancer, dna, mutation, cytidine deaminase, hairpin dna, dna binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 55226.03

Authors

Harjes, S.,Jameson, G.B.,Harjes, E.,Filichev, V.V.,Kurup, H.M. (deposition date: 2022-12-16, release date: 2023-09-06, Last modification date: 2024-09-18)

Primary citation

Harjes, S.,Kurup, H.M.,Rieffer, A.E.,Bayarjargal, M.,Filitcheva, J.,Su, Y.,Hale, T.K.,Filichev, V.V.,Harjes, E.,Harris, R.S.,Jameson, G.B.
Structure-guided inhibition of the cancer DNA-mutating enzyme APOBEC3A.
Nat Commun, 14:6382-6382, 2023

PubMed Abstract: The normally antiviral enzyme APOBEC3A is an endogenous mutagen in human cancer. Its single-stranded DNA C-to-U editing activity results in multiple mutagenic outcomes including signature single-base substitution mutations (isolated and clustered), DNA breakage, and larger-scale chromosomal aberrations. APOBEC3A inhibitors may therefore comprise a unique class of anti-cancer agents that work by blocking mutagenesis, slowing tumor evolvability, and preventing detrimental outcomes such as drug resistance and metastasis. Here we reveal the structural basis of competitive inhibition of wildtype APOBEC3A by hairpin DNA bearing 2'-deoxy-5-fluorozebularine in place of the cytidine in the TC substrate motif that is part of a 3-nucleotide loop. In addition, the structural basis of APOBEC3A's preference for YTCD motifs (Y = T, C; D = A, G, T) is explained. The nuclease-resistant phosphorothioated derivatives of these inhibitors have nanomolar potency in vitro and block APOBEC3A activity in human cells. These inhibitors may be useful probes for studying APOBEC3A activity in cellular systems and leading toward, potentially as conjuvants, next-generation, combinatorial anti-mutator and anti-cancer therapies.

PubMed: 37821454
DOI: 10.1038/s41467-023-42174-w

Experimental method

X-RAY DIFFRACTION (2.01 Å)