Conformational Heterogeneity and Cooperative Effects of Mammalian ALOX15

Igor Ivanov, Alejandro Cruz, Alexander Zhuravlev, Almerinda Di Venere, Eleonora Nicolai, Sabine Stehling, José M. Lluch, Àngels González-Lafont, Hartmut Kuhn

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Arachidonic acid lipoxygenases (ALOXs) have been suggested to function as monomeric enzymes, but more recent data on rabbit ALOX15 indicated that there is a dynamic monomer‐dimer equilibrium in aqueous solution. In the presence of an active site ligand (the ALOX15 inhibitor RS7) rabbit ALOX15 was crystalized as heterodimer and the X‐ray coordinates of the two monomers within the dimer exhibit subtle structural differences. Using native polyacrylamide electrophoresis, we here observed that highly purified and predominantly monomeric rabbit ALOX15 and human ALOX15B are present in two conformers with distinct electrophoretic mobilities. In silico docking studies, molecular dynamics simulations, site directed mutagenesis experiments and kinetic meas-urements suggested that in aqueous solutions the two enzymes exhibit motional flexibility, which may impact the enzymatic properties.

Original languageEnglish
Article number3285
Number of pages18
JournalInternational journal of molecular sciences
Issue number6
Publication statusPublished - 23 Mar 2021


  • Amino Acid Substitution
  • Animals
  • Arachidonate 15-Lipoxygenase/chemistry
  • Catalysis
  • Cooperative effects
  • Crystal structure
  • Humans
  • Isoenzymes
  • Kinetics
  • Lipoxygenases
  • Models, Molecular
  • Molecular dynamics
  • Mutation
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Protein Multimerization
  • Protein–protein interactions
  • Rabbits
  • cooperative effects
  • crystal structure
  • lipoxygenases
  • molecular dynamics
  • protein interactions
  • protein&#8211


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