3RQD
Ideal Thiolate-Zinc Coordination Geometry in Depsipeptide Binding to Histone Deacetylase 8
Summary for 3RQD
| Entry DOI | 10.2210/pdb3rqd/pdb |
| Related PRD ID | PRD_000785 |
| Descriptor | Histone deacetylase 8, Largazole, ZINC ION, ... (5 entities in total) |
| Functional Keywords | histone deacetylase, largazole, histone deacetylation, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (human) More |
| Cellular location | Nucleus: Q9BY41 |
| Total number of polymer chains | 4 |
| Total formula weight | 87852.62 |
| Authors | Cole, K.E.,Dowling, D.P.,Christianson, D.W. (deposition date: 2011-04-28, release date: 2011-08-24, Last modification date: 2024-10-16) |
| Primary citation | Cole, K.E.,Dowling, D.P.,Boone, M.A.,Phillips, A.J.,Christianson, D.W. Structural basis of the antiproliferative activity of largazole, a depsipeptide inhibitor of the histone deacetylases. J.Am.Chem.Soc., 133:12474-12477, 2011 Cited by PubMed Abstract: Largazole is a macrocyclic depsipeptide originally isolated from the marine cyanobacterium Symploca sp., which is indigenous to the warm, blue-green waters of Key Largo, Florida (whence largazole derives its name). Largazole contains an unusual thiazoline-thiazole ring system that rigidifies its macrocyclic skeleton, and it also contains a lipophilic thioester side chain. Hydrolysis of the thioester in vivo yields largazole thiol, which exhibits remarkable antiproliferative effects and is believed to be the most potent inhibitor of the metal-dependent histone deacetylases (HDACs). Here, the 2.14 Å-resolution crystal structure of the HDAC8-largazole thiol complex is the first of an HDAC complexed with a macrocyclic inhibitor and reveals that ideal thiolate-zinc coordination geometry is the key chemical feature responsible for its exceptional affinity and biological activity. Notably, the core structure of largazole is conserved in romidepsin, a depsipeptide natural product formulated as the drug Istodax recently approved for cancer chemotherapy. Accordingly, the structure of the HDAC8-largazole thiol complex is the first to illustrate the mode of action of a new class of therapeutically important HDAC inhibitors. PubMed: 21790156DOI: 10.1021/ja205972n PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.143 Å) |
Structure validation
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