Structural studies of human histone deacetylase 8 and its site-specific variants complexed with substrate and inhibitors.
Structural studies of human histone deacetylase 8 and its site-specific variants complexed with substrate and inhibitors.
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DOI：
10.1021/bi801610c
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发表时间：
2008-12-23
期刊：
影响因子：
2.9
通讯作者：
Christianson, David W.
中科院分区：
文献类型：
--
作者：
Dowling, Daniel P.;Gantt, Stephanie L.;Gattis, Samuel G.;Fierke, Carol A.;Christianson, David W.
金属依赖性组蛋白去乙酰化酶（HDAC）需要Zn ~（2+）或Fe ~（2+）来调节真核细胞中组蛋白和其他蛋白质中赖氨酸残基的乙酰化。同工酶HDAC 8可能是I类HDAC家族的典型成员，并作为研究结构-功能关系的范例。本文报道了HDAC_8与3-（1-甲基-4-苯乙酰基-1H-2-吡咯基）-N -羟基-2-丙烯酰胺（APHA）形成的新型晶体复合物的结构。APHA配合物的结构表明，异羟肟酸C=O基团接受来自Y306的氢键，但不以有利的几何构型与Zn 2+配位，这可能是由于其扩展的π系统的限制。此外，由于APHA仅与该复合物的不对称单元中的3个蛋白质分子中的2个结合，因此第三单体的结构代表HDAC 8在未配体状态下的第一结构。未配体和配体结构的比较说明了L2环中可能伴随底物结合和催化的配体诱导的构象变化。此外，这些结构，连同D101 N、D101 E、D101 A和D101 L变体的结构，沿着支持D101对L2环的功能至关重要的提议。然而，D101的氨基酸取代也可引发Y111和W141的构象变化，从而干扰底物结合位点。最后，与完整的乙酰化四肽底物分子复合的H143 A HDAC 8的结构证实了D101对于底物结合的重要性，并揭示了Y306和活性位点锌离子如何一起结合并激活乙酰赖氨酸的易断裂酰胺键。
Metal-dependent histone deacetylases (HDACs) require Zn2+ or Fe2+ to regulate the acetylation of lysine residues in histones and other proteins in eukaryotic cells. Isozyme HDAC8 is perhaps the archetypical member of the class I HDAC family and serves as a paradigm for studying structure-function relationships. Here, we report the structures of HDAC8 complexes with trichostatin A and 3-(1-methyl-4-phenylacetyl-1H-2-pyrrolyl)-N -hydroxy-2-propenamide (APHA) in a new crystal form. The structure of the APHA complex reveals that the hydroxamate C=O group accepts a hydrogen bond from Y306 but does not coordinate to Zn2+ with favorable geometry, perhaps due to the constraints of its extended π system. Additionally, since APHA binds to only 2 of the 3 protein molecules in the asymmetric unit of this complex, the structure of the third monomer represents the first structure of HDAC8 in the unliganded state. Comparison of unliganded and liganded structures illustrates ligand-induced conformational changes in the L2 loop that likely accompany substrate binding and catalysis. Furthermore, these structures, along with those of the D101N, D101E, D101A, and D101L variants, support the proposal that D101 is critical for the function of the L2 loop. However, amino acid substitutions for D101 can also trigger conformational changes of Y111 and W141 that perturb the substrate binding site. Finally, the structure of H143A HDAC8 complexed with an intact acetylated tetrapeptide substrate molecule confirms the importance of D101 for substrate binding and reveals how Y306 and the active site zinc ion together bind and activate the scissile amide linkage of acetyllysine.
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影响因子：
5.6
作者：
Gregoretti, IV;Lee, YM;Goodson, HV
通讯作者：
Goodson, HV
影响因子：
64.8
作者：
Finnin, MS;Donigian, JR;Pavletich, NP
通讯作者：
Pavletich, NP
影响因子：
4.8
作者：
Bottomley, Matthew J.;Lo Surdo, Paola;Carfi, Andrea
通讯作者：
Carfi, Andrea
影响因子：
2.9
作者：
Cosgrove, MS;Wolberger, C
通讯作者：
Wolberger, C
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL