Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor
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- Alessandro Vannini
- Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; and Department of Medicinal Chemistry, Merck and Company, Inc., Rahway, NJ 07065
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- Cinzia Volpari
- Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; and Department of Medicinal Chemistry, Merck and Company, Inc., Rahway, NJ 07065
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- Gessica Filocamo
- Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; and Department of Medicinal Chemistry, Merck and Company, Inc., Rahway, NJ 07065
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- Elena Caroli Casavola
- Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; and Department of Medicinal Chemistry, Merck and Company, Inc., Rahway, NJ 07065
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- Mirko Brunetti
- Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; and Department of Medicinal Chemistry, Merck and Company, Inc., Rahway, NJ 07065
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- Debora Renzoni
- Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; and Department of Medicinal Chemistry, Merck and Company, Inc., Rahway, NJ 07065
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- Prasun Chakravarty
- Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; and Department of Medicinal Chemistry, Merck and Company, Inc., Rahway, NJ 07065
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- Chantal Paolini
- Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; and Department of Medicinal Chemistry, Merck and Company, Inc., Rahway, NJ 07065
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- Raffaele De Francesco
- Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; and Department of Medicinal Chemistry, Merck and Company, Inc., Rahway, NJ 07065
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- Paola Gallinari
- Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; and Department of Medicinal Chemistry, Merck and Company, Inc., Rahway, NJ 07065
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- Christian Steinkühler
- Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; and Department of Medicinal Chemistry, Merck and Company, Inc., Rahway, NJ 07065
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- Stefania Di Marco
- Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; and Department of Medicinal Chemistry, Merck and Company, Inc., Rahway, NJ 07065
書誌事項
- 公開日
- 2004-10-11
- DOI
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- 10.1073/pnas.0404603101
- 公開者
- Proceedings of the National Academy of Sciences
この論文をさがす
説明
<jats:p>Histone deacetylases (HDACs) are a family of enzymes involved in the regulation of gene expression, DNA repair, and stress response. These processes often are altered in tumors, and HDAC inhibitors have had pronounced antitumor activity with promising results in clinical trials. Here, we report the crystal structure of human HDAC8 in complex with a hydroxamic acid inhibitor. Such a structure of a eukaryotic zinc-dependent HDAC has not be described previously. Similar to bacterial HDAC-like protein, HDAC8 folds in a single α/β domain. The inhibitor and the zinc-binding sites are similar in both proteins. However, significant differences are observed in the length and structure of the loops surrounding the active site, including the presence of two potassium ions in HDAC8 structure, one of which interacts with key catalytic residues. CD data suggest a direct role of potassium in the fold stabilization of HDAC8. Knockdown of HDAC8 by RNA interference inhibits growth of human lung, colon, and cervical cancer cell lines, highlighting the importance of this HDAC subtype for tumor cell proliferation. Our findings open the way for the design and development of selective inhibitors of HDAC8 as possible antitumor agents.</jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 101 (42), 15064-15069, 2004-10-11
Proceedings of the National Academy of Sciences
