Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8–substrate complex

Vannini, Alessandro; Volpari, Cinzia; Gallinari, Paola; Jones, Philip; Mattu, Marco; Carfı́, Andrea; Francesco, Raffaele De; Steinkühler, Christian; Marco, Stefania Di

doi:10.1038/sj.embor.7401047

Cited by 235 publications

(439 citation statements)

References 26 publications

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“…In particular, the two loops harboring the residues coordinating the structural zinc ion moved 10 -20 Å toward the active site, resulting in a much greater similarity to the substrate-bound HDAC8 structure (Fig. 6C) (24). This "closed" conformation of the structural zinc-binding domain also results in the formation of the tunnel proposed to allow product release in other HDACs and not formed in the inhibitor-bound HDAC4cd structures.…”

Section: Structural Basis For the Low Enzymatic Activity Of Class Iiamentioning

confidence: 95%

“…5, A and B). The latter interaction is reminiscent of the one established in HDAC8 by the Tyr 306 hydroxyl group with the carbonyl oxygen of the HA inhibitor (20,21,24). Thus, in HDAC4, W2 could form a similar bond with the reaction intermediate and contribute, albeit less efficiently, to its stabilization and to catalysis.…”

Section: Structural Basis For the Low Enzymatic Activity Of Class Iiamentioning

confidence: 96%

“…However, recent progress includes the structures of a catalytically dead HDAC8 active site mutant bound to an acetyl-lysine peptidic substrate (24) and the class IIa HDAC7 catalytic domain (25).…”

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confidence: 99%

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Structural and Functional Analysis of the Human HDAC4 Catalytic Domain Reveals a Regulatory Structural Zinc-binding Domain

Bottomley¹,

Surdo²,

Giovine³

et al. 2008

Journal of Biological Chemistry

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Histone deacetylases (HDACs) regulate chromatin status and gene expression, and their inhibition is of significant therapeutic interest. To date, no biological substrate for class IIa HDACs has been identified, and only low activity on acetylated lysines has been demonstrated. Here, we describe inhibitor-bound and inhibitor-free structures of the histone deacetylase-4 catalytic domain (HDAC4cd) and of an HDAC4cd active site mutant with enhanced enzymatic activity toward acetylated lysines. The structures presented, coupled with activity data, provide the molecular basis for the intrinsically low enzymatic activity of class IIa HDACs toward acetylated lysines and reveal active site features that may guide the design of class-specific inhibitors. In addition, these structures reveal a conformationally flexible structural zinc-binding domain conserved in all class IIa enzymes. Importantly, either the mutation of residues coordinating the structural zinc ion or the binding of a class IIa selective inhibitor prevented the association of HDAC4 with the N-CoR⅐HDAC3 repressor complex. Together, these data suggest a key role of the structural zinc-binding domain in the regulation of class IIa HDAC functions.

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Section: Structural Basis For the Low Enzymatic Activity Of Class Iiamentioning

confidence: 95%

Section: Structural Basis For the Low Enzymatic Activity Of Class Iiamentioning

confidence: 96%

See 1 more Smart Citation

Structural and Functional Analysis of the Human HDAC4 Catalytic Domain Reveals a Regulatory Structural Zinc-binding Domain

Bottomley¹,

Surdo²,

Giovine³

et al. 2008

Journal of Biological Chemistry

Self Cite

279

321

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“…No significant difference was found between the racemic 2 and its individual enantiomers, which proved to be equipotent against all of the zincdependent HDACs. To gain more insight into this equivalence, a docking analysis of the individual enantiomers of 2 was performed based on the crystal structures of HDAC8 8 and HDAC7, 9 which were chosen as representatives of class I and II HDACs, respectively ( Figure 2). 28 In binding these isoforms, a T-shape arrangement was observed for both enantiomers of ligand 2, which projected its aromatic motifs out from the active site channel toward lipophilic pockets located in opposite directions on the enzyme surface.…”

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confidence: 99%

“…30 In part, our hypothesis is also confirmed by a detailed structural comparison between HDAC1 and HDAC8. 31 Considering the high level of conservation of Phe residues among the HDAC isoforms, [8][9][10][11] these interactions might explain the lack of discrimination between the individual enantiomers.…”

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confidence: 99%

Vorinostat-Like Molecules as Structural, Stereochemical, and Pharmacological Tools

Hanessian

Auzzas

Larsson

et al. 2010

ACS Med. Chem. Lett.

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The inhibitory activity of an ω-alkoxy analogue of the HDAC inhibitor, Vorinostat (SAHA), against the 11 isoforms of HDAC is described and evaluated with regard to structural biology information retrieved through computational methods. Preliminary absorption and metabolism studies were performed, which positioned this compound as a potential candidate for further preclinical studies and delineated measures for improving its pharmacokinetic profile.KEYWORDS HDAC promiscuous inhibitors, SAHA analogues, HDAC1-11 profile, class IIa-specific profile, absorption and metabolism I n spite of the significant progress made in HDAC research, 1-4 the quest for isoform-selective inhibitors continues to present a major challenge. [5][6][7] To date, detailed biostructural information is available only regarding a few among the known 11 metallo-enzymes. 1,[8][9][10][11] Consequently, the design of isoform-and class-selective inhibitors is somewhat arbitrary and derivative. 1,7,[12][13][14] In addition, complete data regarding the factual HDAC profile for most of the early discovered agents are not available, since the development of effective isozyme-based assays is relatively recent. [5][6][7][15][16][17][18] As a consequence of the complex, pleiotropic nature of cancer, promiscuous HDAC inhibitors such as Vorinostat (1) (SAHA, suberoylanilide hydroxamic acid) 19 (Figure 1) seem superior and as safe in the clinic as compared to the few class-specific agents available. [5][6][7]15 Ligand-based approaches are a first-choice solution to delineate the structural requirements for HDAC selectivity, especially with the emergence of ω-aryl alkanoyl hydroxamates such as Vorinostat as clinical candidates. 1,7,[12][13][14] In this regard, simple and readily accessible surrogates are worthy of study, provided that they bear pharmacophoric determinants as close as possible to a maximum common substructural consensus required to target the whole HDAC panel. The judicious inclusion of specific appendages capable of interacting with specific residues in the cap region of HDACs can provide valuable structural, functional, and stereochemical insight into the design of new inhibitors.In a previous study, we determined the optimal alkyl chain length for activity against a single isoform, HDAC2. 20 Designed for understanding the role of the chirality in simple ω-alkoxy analogues of Vorinostat, compound (R/S)-2 emerged as a promising lead for its preliminary cytotoxic activity against leukemia, colon, and lung tumor cell lines. Here, we describe the details for the improved and shortened synthesis of 2, together with the biostructural insights through molecular modeling and a preliminary study of its in vitro activity against an extended panel of HDACs.Although relatively simple in conception, the previous nine-step synthesis of racemic 2 20 was shortened and adapted to produce gram-scale material for pharmacological studies (Supporting Information) (Scheme 1). The required 8-carbon chain of (R/S)-2 was assembled by a cross metathesis reac...

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Histone Deacetylase Inhibitors

Finn¹

2009

Drug Design of Zinc‐Enzyme Inhibitors

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Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8–substrate complex

Cited by 235 publications

References 26 publications

Structural and Functional Analysis of the Human HDAC4 Catalytic Domain Reveals a Regulatory Structural Zinc-binding Domain

Structural and Functional Analysis of the Human HDAC4 Catalytic Domain Reveals a Regulatory Structural Zinc-binding Domain

Vorinostat-Like Molecules as Structural, Stereochemical, and Pharmacological Tools

Histone Deacetylase Inhibitors

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