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. 2021 Sep 22:2:100059.
doi: 10.1016/j.crphar.2021.100059. eCollection 2021.

Interaction of obtusilactone B and related butanolide lactones with the barrier-to-autointegration factor 1 (BAF1). A computational study

Affiliations

Interaction of obtusilactone B and related butanolide lactones with the barrier-to-autointegration factor 1 (BAF1). A computational study

Christian Bailly et al. Curr Res Pharmacol Drug Discov. .

Abstract

The barrier-to-autointegration factor 1 (BAF1) protein is a DNA-binding protein implicated in nuclear envelop repair and reformation after mitosis. This nuclear protein is frequently overexpressed in cancer cells and plays a role in the occurrence and development of different tumors. It is a potential therapeutic target for gastric cancer, breast cancer and other malignancies. For this reason, BAF1 inhibitors are searched. The butanolide lactone obtusilactone B (Ob-B) has been found to inhibit VRK1-dependent phosphorylation of BAF1, upon direct binding to the nuclear protein. Taking advantage of the known crystallographic structure of BAF1, we have elaborated molecular models of Ob-B bound to BAF1 to delimit the binding site and binding configuration. The long endoolefinic alkyl side chain of Ob-B extends into a small groove on the protein surface, and the adjacent exomethylene-γ-lactone moiety occupies a pocket comprising to the Ser-4 phosphorylation site of BAF1. Twenty butanolide lactones structurally close to ObB were screened for BAF1 binding. Several natural products with BAF1-binding capacity potentially superior to Ob-B were identified, including mahubanolide, kotomolide B, epilitsenolide D2, and a few other known anticancer plant natural products. Our study provides new ideas to guide the discovery and design of BAF1 inhibitors.

Keywords: BAF1, Barrier-to-Autointegration Factor 1; Barrier-to-autointegration factor 1; Butanolide lactones; Cancer; Ob-B, obtusilactone B; Obtusilactone; VRK1, vaccinia-related kinase 1.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
(a) Structure of obtusilactone B (Ob-B). (b) A model of the compound bound to the ternary complex formed between BAF1 (in green), emerin (in cyan) and DNA (blue and red strands). (c) A close-up view of Ob-B lying in a groove at the surface of BAF1, lying from the DNA side to the emerin side. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Fig. 2
Molecular model of Ob-B bound to BAF1. (a) The compound extends along the protein surface and fits into a groove over the entire length of the protein (green). Panels (b and c) show a detailed view of the compound in the binding site, with (b) the H-bond donor/acceptor groups and (c) the solvent-accessible surface (SAS) defined. (d) Binding map contacts for Ob-B bound to BAF1. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
Fig. 3
Superimposed models of the crystallographic structure of BAF1 (PDB: 1CI4, in green) and our model of Ob-B bound to BAF1 (in cyan). The Ser-4 residue corresponds to the phosphorylation site of BAF1. This residue lies in a non-structured flexible region of the protein. A conformational analysis (Monte Carlo) of this domain has been performed, leading to the Ob-B-BAF1 complex with an O–O distance of 2.726 ​Å between the Ser-4 OH residue and the O-lactone of Ob-B. The distance is compatible with the formation of a H-bond interaction. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 4
Fig. 4
Structures of the tested butanolide derivatives.
Fig. 5
Fig. 5
Molecular model of four selected butanolides bound to BAF1. In each case, the compound bound to the BAF1 protein (in green) is presented, together with a close-up view of the compound-binding site (solvent-accessible surface (SAS) with the indicated color code). A binding map for each compound is also included. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 6
Fig. 6
Superimposed models of BAF1 and the indicated butanolide derivatives. Both epilitsenolide D2 and kotomolide B bind preferentially into a groove on the protein surface distinct from that occupied by Ob-B, whereas mahubanolide binds essentially to the same site as Ob-B.

References

    1. Bailly C. Anticancer butanolides and lignans from the makko tree, Machilus thunbergii Sieb. & Zucc. Trends Phytochem. Res. 2021;5:136–147.
    1. Bengtsson L., Wilson K.L. Barrier-to-autointegration factor phosphorylation on Ser-4 regulates emerin binding to lamin A in vitro and emerin localization in vivo. Mol. Biol. Cell. 2006;17:1154–1163. - PMC - PubMed
    1. Bradley C.M., Ronning D.R., Ghirlando R., Craigie R., Dyda F. Structural basis for DNA bridging by barrier-to-autointegration factor. Nat. Struct. Mol. Biol. 2005;12:935–936. - PubMed
    1. Burger M., Schmitt-Koopmann C., Leroux J.C. DNA unchained: two assays to discover and study inhibitors of the DNA clustering function of barrier-to-autointegration factor. Sci. Rep. 2020;10:12301. - PMC - PubMed
    1. Burgess J.T., Cheong C.M., Suraweera A., Sobanski T., Beard S., Dave K., Rose M., Boucher D., Croft L.V., Adams M.N., O'Byrne K., Richard D.J., Bolderson E. Barrier-to-autointegration-factor (Banf1) modulates DNA double-strand break repair pathway choice via regulation of DNA-dependent kinase (DNA-PK) activity. Nucleic Acids Res. 2021;49:3294–3307. - PMC - PubMed

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