ALKBH7 Variant Related to Prostate Cancer Exhibits Altered Substrate Binding.
| Autor: | Alice R Walker, Pavel Silvestrov, Tina A Müller, Robert H Podolsky, Gregory Dyson, Robert P Hausinger, Gerardo Andrés Cisneros |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | PLoS Computational Biology, Vol 13, Iss 2, p e1005345 (2017) |
| Druh dokumentu: | article |
| ISSN: | 1553-734X 1553-7358 |
| DOI: | 10.1371/journal.pcbi.1005345 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
| Externí odkaz: |
|