Homology modeling, molecular dynamics, and site-directed mutagenesis study of AlkB human homolog 1 (ALKBH1).

The ability to repair DNA is important for the conservation of genetic information of living organisms. Cells have a number of ways to restore damaged DNA, such as direct DNA repair, base excision repair, and nucleotide excision repair. One of the proteins that can perform direct repair of DNA bases is Escherichia coli AlkB. In humans, there are 9 identified AlkB homologs, including AlkB homolog 1 (ALKBH1). Many of these proteins catalyze the direct oxidative dealkylation of DNA and RNA bases and, as such, have an important role in repairing DNA from damage induced by alkylating agents. In addition to the dealkylase activity, ALKBH1 can also function as an apyrimidinic/apurinic lyase and was proposed to have a distinct lyase active site. To our knowledge, no crystal structure or complete homology model of ALKBH1 protein is available. In this study, we have used homology modeling to predict the structure of ALKBH1 based on AlkB and Duffy-binding-like domain crystal structures as templates. Molecular dynamics simulations were subsequently performed on the predicted structure of ALKBH1. The positions of two disulfide bonds or a zinc-finger motif and a disulfide bond were predicted and the importance of these features was tested by mutagenesis. Possible locations for the lyase active site are proposed based on the analysis of our predicted structures and previous experimental results. Copyright © 2014 Elsevier Inc. All rights reserved.

Citation

Pavel Silvestrov, Tina A Müller, Kristen N Clark, Robert P Hausinger, G Andrés Cisneros. Homology modeling, molecular dynamics, and site-directed mutagenesis study of AlkB human homolog 1 (ALKBH1). Journal of molecular graphics & modelling. 2014 Nov;54:123-30

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PMID: 25459764

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