title: Insights into the mechanism of binding of arachidonic acid to mammalian 15-lipoxygenases.
abstract: Mammalian 15-lipoxygenases (15-LOs) are key pharmaceutical targets under strong investigation because of their implication in atherosclerosis and cancer. Here, we present an atomic-level study of the binding modes of arachidonic acid (AA) to rabbit reticulocyte 15-LO, with a particular insight into the 15-LO:AA complexes consistent with known catalytic activity. We take into account both ligand and protein flexibility, by combining protein-ligand docking techniques and molecular dynamics simulations. We have also performed in silico mutagenesis. Our results are in agreement with previous mutagenesis data, in particular with the importance of Arg403 on AA binding. Interestingly, our results also reveal a central role of Arg403 in the conformational change of the alpha2-helix observed upon ligand binding. That induced-fit effect could give a possible framework for the molecular explanation of the known allosteric effect and questions the suitability of the inhibitor-bound crystal structure for accepting AA. Accounting for these dynamical considerations might improve the drug design process.
authors.affiliation: Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors.forename: Lea
authors.initials: L
authors.lastname: Toledo
authors.forename: Laura
authors.initials: L
authors.lastname: Masgrau
authors.forename: Jean-Didier
authors.initials: JD
authors.lastname: Maréchal
authors.forename: José M
authors.initials: JM
authors.lastname: Lluch
authors.forename: Angels
authors.initials: A
authors.lastname: González-Lafont
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000737:chemistry* / Q000378:metabolism; D016718:Arachidonic Acid / Q000737:chemistry*; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011817:Rabbits; D012156:Reticulocytes / Q000201:enzymology
chemical_list: D008024:Ligands; D016718:Arachidonic Acid; D001093:Arachidonate 15-Lipoxygenase