4RN0

Crystal structure of S39D HDAC8 in complex with a largazole analogue.

4RN0 の概要

• エントリーDOI: 10.2210/pdb4rn0/pdb
• 関連するPDBエントリー: 4RN1 4RN2
• 分子名称: Histone deacetylase 8, (5R,8S,11S)-5-methyl-8-(propan-2-yl)-11-[(1E)-4-sulfanylbut-1-en-1-yl]-3,17-dithia-7,10,14,19,20-pentaazatricyclo[14.2.1.1~2,5~]icosa-1(18),2(20),16(19)-triene-6,9,13-trione, ZINC ION, ... (7 entities in total)
• 機能のキーワード: metalloenzyme, hydrolase, histone deacetylase, enzyme inhibitor complex, largazole analogue, thiol inhibitor, arginase/deacetylase fold, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: Q9BY41
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 87959.75

構造登録者

Decroos, C.,Christianson, D.W. (登録日: 2014-10-22, 公開日: 2015-04-08, 最終更新日: 2023-09-20)

主引用文献

Decroos, C.,Clausen, D.J.,Haines, B.E.,Wiest, O.,Williams, R.M.,Christianson, D.W.
Variable Active Site Loop Conformations Accommodate the Binding of Macrocyclic Largazole Analogues to HDAC8.
Biochemistry, 54:2126-2135, 2015

PubMed Abstract: The macrocyclic depsipeptide Largazole is a potent inhibitor of metal-dependent histone deacetylases (HDACs), some of which are drug targets for cancer chemotherapy. Indeed, Largazole partially resembles Romidepsin (FK228), a macrocyclic depsipeptide already approved for clinical use. Each inhibitor contains a pendant side chain thiol that coordinates to the active site Zn(2+) ion, as observed in the X-ray crystal structure of the HDAC8-Largazole complex [Cole, K. E., Dowling, D. P., Boone, M. A., Phillips, A. J., and Christianson, D. W. (2011) J. Am. Chem. Soc. 133, 12474]. Here, we report the X-ray crystal structures of HDAC8 complexed with three synthetic analogues of Largazole in which the depsipeptide ester is replaced with a rigid amide linkage. In two of these analogues, a six-membered pyridine ring is also substituted (with two different orientations) for the five-membered thiazole ring in the macrocycle skeleton. The side chain thiol group of each analogue coordinates to the active site Zn(2+) ion with nearly ideal geometry, thereby preserving the hallmark structural feature of inhibition by Largazole. Surprisingly, in comparison with the binding of Largazole, these analogues trigger alternative conformational changes in loops L1 and L2 flanking the active site. However, despite these structural differences, inhibitory potency is generally comparable to, or just moderately less than, the inhibitory potency of Largazole. Thus, this study reveals important new structure-affinity relationships for the binding of macrocyclic inhibitors to HDAC8.

PubMed: 25793284
DOI: 10.1021/acs.biochem.5b00010

実験手法

X-RAY DIFFRACTION (1.761 Å)