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Seeding for sirtuins: microseed matrix seeding to obtain crystals of human Sirt3 and Sirt2 suitable for soaking.

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Rumpf T, Gerhardt S, Einsle O, Jung M
OpenAccess logo Acta Crystallogr F Struct Biol Commun 71 1498-510 (2015)
Related entries: 5d7o, 5d7p, 5d7q

Cited: 21 times
EuropePMC logo PMID: 26625292

Abstract

Sirtuins constitute a family of NAD(+)-dependent enzymes that catalyse the cleavage of various acyl groups from the ℇ-amino group of lysines. They regulate a series of cellular processes and their misregulation has been implicated in various diseases, making sirtuins attractive drug targets. To date, only a few sirtuin modulators have been reported that are suitable for cellular research and their development has been hampered by a lack of structural information. In this work, microseed matrix seeding (MMS) was used to obtain crystals of human Sirt3 in its apo form and of human Sirt2 in complex with ADP ribose (ADPR). Crystal formation using MMS was predictable, less error-prone and yielded a higher number of crystals per drop than using conventional crystallization screening methods. The crystals were used to solve the crystal structures of apo Sirt3 and of Sirt2 in complex with ADPR at an improved resolution, as well as the crystal structures of Sirt2 in complex with ADPR and the indoles EX527 and CHIC35. These Sirt2-ADPR-indole complexes unexpectedly contain two indole molecules and provide novel insights into selective Sirt2 inhibition. The MMS approach for Sirt2 and Sirt3 may be used as the basis for structure-based optimization of Sirt2/3 inhibitors in the future.

Reviews - 5d7n mentioned but not cited (1)

  1. Virtual Screening in the Identification of Sirtuins' Activity Modulators. Abbotto E, Scarano N, Piacente F, Millo E, Cichero E, Bruzzone S. Molecules 27 5641 (2022)

Articles - 5d7n mentioned but not cited (4)

  1. Seeding for sirtuins: microseed matrix seeding to obtain crystals of human Sirt3 and Sirt2 suitable for soaking. Rumpf T, Gerhardt S, Einsle O, Jung M. Acta Crystallogr F Struct Biol Commun 71 1498-1510 (2015)
  2. How Many Sirtuin Genes Are Out There? Evolution of Sirtuin Genes in Vertebrates With a Description of a New Family Member. Opazo JC, Vandewege MW, Hoffmann FG, Zavala K, Meléndez C, Luchsinger C, Cavieres VA, Vargas-Chacoff L, Morera FJ, Burgos PV, Tapia-Rojas C, Mardones GA. Mol Biol Evol 40 msad014 (2023)
  3. Resveratrol analog, triacetylresveratrol, a potential immunomodulator of lung adenocarcinoma immunotherapy combination therapies. He J, Qiu N, Zhou X, Meng M, Liu Z, Li J, Du S, Sun Z, Wang H. Front Oncol 12 1007653 (2022)
  4. A flexible data-free framework for structure-based de novo drug design with reinforcement learning. Du H, Jiang D, Zhang O, Wu Z, Gao J, Zhang X, Wang X, Deng Y, Kang Y, Li D, Pan P, Hsieh CY, Hou T. Chem Sci 14 12166-12181 (2023)


Reviews citing this publication (8)

  1. Lysine Acetylation Goes Global: From Epigenetics to Metabolism and Therapeutics. Ali I, Conrad RJ, Verdin E, Ott M. Chem Rev 118 1216-1252 (2018)
  2. The Current State of NAD+ -Dependent Histone Deacetylases (Sirtuins) as Novel Therapeutic Targets. Schiedel M, Robaa D, Rumpf T, Sippl W, Jung M. Med Res Rev 38 147-200 (2018)
  3. SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases. Manjula R, Anuja K, Alcain FJ. Front Pharmacol 11 585821 (2020)
  4. Sirtuins and their Biological Relevance in Aging and Age-Related Diseases. Zhao L, Cao J, Hu K, He X, Yun D, Tong T, Han L. Aging Dis 11 927-945 (2020)
  5. Guidelines for the successful generation of protein-ligand complex crystals. Müller I. Acta Crystallogr D Struct Biol 73 79-92 (2017)
  6. Human sirtuins: Structures and flexibility. Sacconnay L, Carrupt PA, Nurisso A. J Struct Biol 196 534-542 (2016)
  7. Opening the Selectivity Pocket in the Human Lysine Deacetylase Sirtuin2 - New Opportunities, New Questions. Robaa D, Monaldi D, Wössner N, Kudo N, Rumpf T, Schiedel M, Yoshida M, Jung M. Chem Rec 18 1701-1707 (2018)
  8. The roles of sirtuins in ferroptosis. Zeng J, Guo J, Huang S, Cheng Y, Luo F, Xu X, Chen R, Ma G, Wang Y. Front Physiol 14 1131201 (2023)

Articles citing this publication (8)

  1. Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives. You W, Zheng W, Weiss S, Chua KF, Steegborn C. Sci Rep 9 19176 (2019)
  2. New chemical tools for probing activity and inhibition of the NAD+-dependent lysine deacylase sirtuin 2. Swyter S, Schiedel M, Monaldi D, Szunyogh S, Lehotzky A, Rumpf T, Ovádi J, Sippl W, Jung M. Philos Trans R Soc Lond B Biol Sci 373 20170083 (2018)
  3. Identification of Bichalcones as Sirtuin Inhibitors by Virtual Screening and In Vitro Testing. Karaman B, Alhalabi Z, Swyter S, Mihigo SO, Andrae-Marobela K, Jung M, Sippl W, Ntie-Kang F. Molecules 23 E416 (2018)
  4. Mechanism-based inhibitors of SIRT2: structure-activity relationship, X-ray structures, target engagement, regulation of α-tubulin acetylation and inhibition of breast cancer cell migration. Nielsen AL, Rajabi N, Kudo N, Lundø K, Moreno-Yruela C, Bæk M, Fontenas M, Lucidi A, Madsen AS, Yoshida M, Olsen CA. RSC Chem Biol 2 612-626 (2021)
  5. The crystal structure of the Leishmania infantum Silent Information Regulator 2 related protein 1: Implications to protein function and drug design. Ronin C, Costa DM, Tavares J, Faria J, Ciesielski F, Ciapetti P, Smith TK, MacDougall J, Cordeiro-da-Silva A, Pemberton IK. PLoS One 13 e0193602 (2018)
  6. Three-Component Aminoalkylations Yielding Dihydronaphthoxazine-Based Sirtuin Inhibitors: Scaffold Modification and Exploration of Space for Polar Side-Chains. Vojacek S, Beese K, Alhalabi Z, Swyter S, Bodtke A, Schulzke C, Jung M, Sippl W, Link A. Arch Pharm (Weinheim) 350 (2017)
  7. Substrate-Dependent Modulation of SIRT2 by a Fluorescent Probe, 1-Aminoanthracene. Bi D, Yang J, Hong JY, Parikh P, Hinds N, Infanti J, Lin H, Weiser BP. Biochemistry 59 3869-3878 (2020)
  8. Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors. Scarano N, Abbotto E, Musumeci F, Salis A, Brullo C, Fossa P, Schenone S, Bruzzone S, Cichero E. Int J Mol Sci 24 9363 (2023)


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