5SXG

Crystal Structure of the Cancer Genomic DNA Mutator APOBEC3B

Summary for 5SXG

• Entry DOI: 10.2210/pdb5sxg/pdb
• Descriptor: DNA dC->dU-editing enzyme APOBEC-3B, ZINC ION, 1,3-PROPANDIOL, ... (5 entities in total)
• Functional Keywords: apobec, deaminase, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 44299.84

Authors

Shi, K.,Kurahashi, K.,Aihara, H. (deposition date: 2016-08-09, release date: 2017-12-27, Last modification date: 2023-10-04)

Primary citation

Shi, K.,Demir, O.,Carpenter, M.A.,Wagner, J.,Kurahashi, K.,Harris, R.S.,Amaro, R.E.,Aihara, H.
Conformational Switch Regulates the DNA Cytosine Deaminase Activity of Human APOBEC3B.
Sci Rep, 7:17415-17415, 2017

PubMed Abstract: The APOBEC3B (A3B) single-stranded DNA (ssDNA) cytosine deaminase has important roles in innate immunity but is also a major endogenous source of mutations in cancer. Previous structural studies showed that the C-terminal catalytic domain of human A3B has a tightly closed active site, and rearrangement of the surrounding loops is required for binding to substrate ssDNA. Here we report structures of the A3B catalytic domain in a new crystal form that show alternative, yet still closed, conformations of active site loops. All-atom molecular dynamics simulations support the dynamic behavior of active site loops and recapitulate the distinct modes of interactions that maintain a closed active site. Replacing segments of A3B loop 1 to mimic the more potent cytoplasmic deaminase APOBEC3A leads to elevated ssDNA deaminase activity, likely by facilitating opening of the active site. These data collectively suggest that conformational equilibrium of the A3B active site loops, skewed toward being closed, controls enzymatic activity by regulating binding to ssDNA substrates.

PubMed: 29234087
DOI: 10.1038/s41598-017-17694-3

Experimental method

X-RAY DIFFRACTION (1.93 Å)