title: Rational design of an auxin antagonist of the SCF(TIR1) auxin receptor complex.
abstract: The plant hormone auxin is a master regulator of plant growth and development. By regulating rates of cell division and elongation and triggering specific patterning events, indole 3-acetic acid (IAA) regulates almost every aspect of plant development. The perception of auxin involves the formation of a ternary complex consisting of an F-box protein of the TIR1/AFB family of auxin receptors, the auxin molecule, and a member the Aux/IAA family of co-repressor proteins. In this study, we identified a potent auxin antagonist, α-(phenylethyl-2-oxo)-IAA, as a lead compound for TIR1/AFB receptors by in silico virtual screening. This molecule was used as the basis for the development of a more potent TIR1 antagonist, auxinole (α-[2,4-dimethylphenylethyl-2-oxo]-IAA), using a structure-based drug design approach. Auxinole binds TIR1 to block the formation of the TIR1-IAA-Aux/IAA complex and so inhibits auxin-responsive gene expression. Molecular docking analysis indicates that the phenyl ring in auxinole would strongly interact with Phe82 of TIR1, a residue that is crucial for Aux/IAA recognition. Consistent with this predicted mode of action, auxinole competitively inhibits various auxin responses in planta. Additionally, auxinole blocks auxin responses of the moss Physcomitrella patens, suggesting activity over a broad range of species. Our works not only substantiates the utility of chemical tools for plant biology but also demonstrates a new class of small molecule inhibitor of protein-protein interactions common to mechanisms of perception of other plant hormones, such as jasmonate, gibberellin, and abscisic acid.
authors.affiliation: Department of Biochemistry, Okayama University of Science, Okayama 700-0005, Japan. hayashi@dbc.ous.ac.jp
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Joshua
authors.initials: J
authors.lastname: Neve
authors.forename: Masakazu
authors.initials: M
authors.lastname: Hirose
authors.forename: Atsuhito
authors.initials: A
authors.lastname: Kuboki
authors.forename: Yukihisa
authors.initials: Y
authors.lastname: Shimada
authors.forename: Stefan
authors.initials: S
authors.lastname: Kepinski
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nozaki
mesh_terms: D017360:Arabidopsis / Q000737:chemistry / Q000254:growth & development; D029681:Arabidopsis Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D044783:F-Box Proteins / Q000037:antagonists & inhibitors*; D007210:Indoleacetic Acids / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D029681:Arabidopsis Proteins; D044783:F-Box Proteins; D007210:Indoleacetic Acids; D011956:Receptors, Cell Surface; C501405:TIR1 protein, Arabidopsis; C574629:alpha-(2,4-dimethylphenylethyl-2-oxo)indole-3-acetic acid; C574628:alpha-(phenylethyl-2-oxo)indole-3-acetic acid