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Binding site for activator MDL-801 on SIRT6

Nature Chemical Biology volume 17, pages 519–521 (2021)Cite this article

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Matters Arising to this article was published on 01 March 2021

The Original Article was published on 29 October 2018

arising from Z. Huang et al. Nature Chemical Biology https://doi.org/10.1038/s41589-018-0150-0 (2018)

In our structure of the SIRT6–MDL-801 complex, the activator’s 5-bromo-4-fluoro-2-methylaniline moiety is packed in a hydrophobic pocket formed by Val 115, Val 70, Phe 64 and Phe 82/Phe 86 and lined by Pro 62, the main chain oxygen of which appears to form a halogen bond with the bromine (Fig. 2b and Extended Data Fig. 1d). The central 5-amino-2-methylbenzoate moiety is positioned in the acyl channel exit, sandwiched between Met 157 and a hydrophobic patch formed by Val 70 and Trp 71. The terminal 3,5-dichlorobenzenesulfonate is less well defined. It appears to be largely solvent exposed, positioned on the edge of the acyl channel formed by Pro 10 (attributed to a cloning artifact), Asp 187 and Trp 188. Weak electron density and lack of pronounced SIRT6 interactions indicate flexibility for this terminal moiety (see also below). Interaction details, electron density fit and B factors (increasing from ~55 Å2 to ~120 Å2) thus suggest that the high potency of MDL-801 depends on tight interaction of its bromoaniline end with the Pro 62 pocket, in line with the pronounced effects of mutating Phe 82 and Phe 86 on potency2.

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Fig. 1: Electron density and biochemical data indicate MES rather than MDL-801 as the SIRT6 ligand in the previously published structure (PDB ID 5Y2F).
Fig. 2: Crystal structure of the SIRT6–MDL-801 complex.

Data availability

X-ray diffraction data and coordinates for the structures newly reported here have been deposited with the wwPDB (https://www.wwpdb.org/) under accession numbers 6XV1 (SIRT613–308–MDL-801), 6XUY (SIRT613–308 with no activator added), 6XVG (SIRT63–318–MDL-801) and 6XV6 (SIRT63–318 with no activator added). The previously published structure is available under accession number 5Y2F.

References

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Acknowledgements

We thank the Deutsche Forschungsgemeinschaft for financial support (grant STE1701/15).

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Authors and Affiliations

  1. Department of Biochemistry, University of Bayreuth, Bayreuth, Germany

    Weijie You & Clemens Steegborn

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  1. Weijie You
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  2. Clemens Steegborn
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Contributions

Methodology, activity assays, structure determination, data analysis and visualization, and manuscript writing were performed by W.Y. and C.S. Conceptualization, manuscript drafting, supervision and funding acquisition were performed by C.S.

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Correspondence to Clemens Steegborn.

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Competing interests

C.S. is a scientific advisory board member of Ovibio.

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Extended data

Extended Data Fig. 1 Crystal structures of Sirt6 complexes with MDL-801.

a, MDL-801 binding site region in the Sirt613–308 reference structure (not soaked with MDL-801). The 2Fo-Fc electron density (ED) is contoured at 1σ, and the anomalous density at 4σ. b, Zn2+-site of the Sirt63–318/MDL-801 complex and c, of the Sirt613–308 reference structure. The anomalous ED is contoured at 3σ. d, Scheme of the interactions between Sirt613–308 and MDL-801. e, Zn2+-site of the Sirt63–318 reference structure and f, the Sirt63–318/MDL-801 complex, respectively, overlaid with anomalous ED contoured at 3σ. g, Scheme of the interactions between Sirt63–318 and MDL-801. h, Overlay of the different MDL-801 conformations in the six copies of the complex in the asymmetric unit.

Supplementary information

Supplementary Information

Supplementary Methods and Table 1.

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You, W., Steegborn, C. Binding site for activator MDL-801 on SIRT6. Nat Chem Biol 17, 519–521 (2021). https://doi.org/10.1038/s41589-021-00749-y

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