Computational analysis of R and S isoforms of 12-lipoxygenases: homology modeling and docking studies

The present study is aimed at predicting human 12R-LOX structure by constructing a homology model. Based upon Blast results, rabbit reticulocyte 15-lipoxygenase 1LOX (protein data bank) was considered as a template for homology modeling. The 3D model was generated with Modeler in InsightII and further refined using AMBER. Further to understand the relationship of protein structure with stereo specificity, a comparative analysis of 12R-LOX model was done with that of 12S-LOX homology model to identify differences in the binding site topology and interacting residues. The large insertion of 31-aa seen in 12R-LOX is located beyond the N-terminal barrel and is accommodated on the outside of the protein without disruption of the overall tertiary structure. The 31-aa region includes SH3 domain binding PXXP motif, seven prolines and five arginines. The docking of the substrate, arachidonic acid was also performed. Our results show that the Gly441 and substrate orientation within the active site play an important role in stereo specificity of 12R-LOX.