Binding site for activator MDL-801 on SIRT6

You, W.; Steegborn, Clemens

doi:10.1038/s41589-021-00749-y

Cited by 15 publications

(17 citation statements)

References 5 publications

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“…Its hydrogen bond with a hydrophilic patch on the target surface should allow improvement of other ligands with respect to affinity as well as solubility. This includes MDL-801, a more recently identified, micromolar Sirt6 activator (EC 50 10 μM), which was reported to bind to a neighboring, more exposed side but was now shown to share significant interactions with UBCS039 and fluvastatin …”

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confidence: 99%

“…This includes MDL-801, a more recently identified, micromolar Sirt6 activator (EC 50 10 μM), which was reported to bind to a neighboring, more exposed side 13 but was now shown to share significant interactions with UBCS039 and fluvastatin. 25 Statins can induce the sterol regulatory element-binding protein, a key regulator of cholesterol homeostasis, and such an effect has also been attributed to the Sirt6 histone deacetylation activity. 26,27 Thus, Sirt6 modulation might contribute to physiological fluvastatin effects and the molecular details of the Sirt6/fluvastatin interaction thus could also help to improve fluvastatin specificity for its intended target, HMG-CoA reductase.…”

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confidence: 99%

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Structural Basis for Activation of Human Sirtuin 6 by Fluvastatin

You

Steegborn

2020

ACS Med. Chem. Lett.

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Sirtuins are NAD + -dependent protein lysine deacylases that are considered attractive drug targets for agingrelated diseases. Sirt6 deacetylates, e.g., transcription factors and histone H3, and regulates metabolic processes and stress responses. It has been implicated in lifespan extension and tumor suppression. Sirt6 deacetylase activity can be stimulated with small molecules, and fluvastatin, an FDA-approved synthetic statin, was recently described as a novel Sirt6 activator. We studied the molecular details of this effect on Sirt6 in deacylation assays and by solving a crystal structure of a Sirt6/fluvastatin complex. We find that fluvastatin inhibits Sirt1−3 at higher concentrations but has a unique, activating effect on Sirt6. The complex structure reveals that fluvastatin occupies the Sirt6 substrate acyl channel exit, similar to other, unrelated activator families, providing interaction details that will support the development of potent, druglike Sirt6 activators.

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confidence: 99%

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confidence: 99%

Structural Basis for Activation of Human Sirtuin 6 by Fluvastatin

You

Steegborn

2020

ACS Med. Chem. Lett.

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“…The central 2-carboxybenzenesulfonamide ring is also involved in π-stacking interactions with Phe86, whose importance was confirmed by single-residue mutation experiments showing decreased potency of both 7a and 7b toward SIRT6-F86A . However, a recent report from You and Steegborn argued that the observed electron density could be attributed to a molecule of morpholinoethanesulfonic acid (MES), used as crystallization buffer, rather than 7b . Therefore, they determined new crystal structures for SIRT6 in complex with 7b .…”

Section: Pharmacological Modulation Of Sirt6mentioning

confidence: 67%

“… 124 , 125 This discovery paved the way for the development of further activators, such as 7a . 128 Although the binding mode of the analogue 7b raised some discussion, 130 , 131 it is possible that both proposed models are valid in different conditions, and this controversy reminds us that ligand–protein interactions cannot be always recapitulated by a single-crystal structure. In any case, both 7a and its derivative 7c ( 132 ) inhibited tumor growth in xenograft models, showing SIRT6 activation efficacy in vivo for the first time.…”

Section: Discussionmentioning

confidence: 99%

“… 128 However, a recent report from You and Steegborn argued that the observed electron density could be attributed to a molecule of morpholinoethanesulfonic acid (MES), used as crystallization buffer, rather than 7b . 130 Therefore, they determined new crystal structures for SIRT6 in complex with 7b . They solved the cocrystal of N -terminal truncated SIRT6 13–308 in complex with ADP–ribose and 7b (PDB ID: 6XV1) as well as in the absence of 7b (PDB ID: 6XUY).…”

Section: Pharmacological Modulation Of Sirt6mentioning

confidence: 99%

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Emerging Therapeutic Potential of SIRT6 Modulators

2021

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Sirtuin 6 (SIRT6) is an NAD + -dependent protein deacylase and mono-ADP-ribosyltransferase of the sirtuin family with a wide substrate specificity. In vitro and in vivo studies have indicated that SIRT6 overexpression or activation has beneficial effects for cellular processes such as DNA repair, metabolic regulation, and aging. On the other hand, SIRT6 has contrasting roles in cancer, acting either as a tumor suppressor or promoter in a context-specific manner. Given its central role in cellular homeostasis, SIRT6 has emerged as a promising target for the development of small-molecule activators and inhibitors possessing a therapeutic potential in diseases ranging from cancer to age-related disorders. Moreover, specific modulators allow the molecular details of SIRT6 activity to be scrutinized and further validate the enzyme as a pharmacological target. In this Perspective, we summarize the current knowledge about SIRT6 pharmacology and medicinal chemistry and describe the features of the activators and inhibitors identified so far.

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Substrates and Cyclic Peptide Inhibitors of the Oligonucleotide‐Activated Sirtuin 7**

Bolding,

Nielsen,

Jensen

et al. 2023

Angewandte Chemie

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The sirtuins are NAD+‐dependent lysine deacylases, comprising seven isoforms (SIRT1–7) in humans, which are involved in the regulation of a plethora of biological processes, including gene expression and metabolism. The sirtuins share a common hydrolytic mechanism but display preferences for different ε‐N‐acyllysine substrates. SIRT7 deacetylates targets in nuclei and nucleoli but remains one of the lesser studied of the seven isoforms; in part, due to a lack of chemical tools to specifically probe SIRT7 activity. Here we expressed SIRT7 and, using small‐angle X‐ray scattering, reveal SIRT7 to be a monomeric enzyme with low degree of globular flexibility in solution. We developed a fluorogenic assay for investigation of the substrate preferences of SIRT7 and to evaluate compounds that modulate its activity. We report several mechanism‐based SIRT7 inhibitors as well as de novo cyclic peptide inhibitors selected from mRNA‐display library screening that exhibit selectivity for SIRT7 over other sirtuin isoforms, stabilize SIRT7 in cells, and cause increase in the acetylation H3K18.

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Binding site for activator MDL-801 on SIRT6

Cited by 15 publications

References 5 publications

Structural Basis for Activation of Human Sirtuin 6 by Fluvastatin

Structural Basis for Activation of Human Sirtuin 6 by Fluvastatin

Emerging Therapeutic Potential of SIRT6 Modulators

Substrates and Cyclic Peptide Inhibitors of the Oligonucleotide‐Activated Sirtuin 7**

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