ALKBH7 Variant Related to Prostate Cancer Exhibits Altered Substrate Binding

作者：Walker Alice R; Silvestrov Pavel; Mueller Tina A; Podolsky Robert H; Dyson Gregory; Hausinger Robert P; Cisneros Gerardo Andres^*

来源：PLoS Computational Biology, 2017, 13(2): e1005345.

DOI：10.1371/journal.pcbi.1005345

The search for prostate cancer biomarkers has received increased attention and several DNA repair related enzymes have been linked to this dysfunction. Here we report a targeted search for single nucleotide polymorphisms (SNPs) and functional impact characterization of human ALKBH family dioxygenases related to prostate cancer. Our results uncovered a SNP of ALKBH7, rs7540, which is associated with prostate cancer disease in a statistically significantly manner in two separate cohorts, and maintained in African American men. Comparisons of molecular dynamics (MD) simulations on the wild-type and variant protein structures indicate that the resulting alteration in the enzyme induces a significant structural change that reduces ALKBH7's ability to bind its cosubstrate. Experimental spectroscopy studies with purified proteins validate our MD predictions and corroborate the conclusion that this cancer-associated mutation affects productive cosubstrate binding in ALKBH7.

• 出版日期2017-2