Histone deacetylase 6 structure and molecular basis of catalysis and inhibition

@article{Hai2016HistoneD6,
  title={Histone deacetylase 6 structure and molecular basis of catalysis and inhibition},
  author={Y. Hai and D. Christianson},
  journal={Nature chemical biology},
  year={2016},
  volume={12},
  pages={741 - 747}
}
Histone deacetylase 6 (HDAC6) is a critical target for drug design due to its role in oncogenic transformation and cancer metastasis, and is unique among all histone deacetylases in that it contains tandem catalytic domains designated CD1 and CD2. We now report the crystal structures of CD2 from Homo sapiens and CD1 and CD2 from Danio rerio HDAC6, and we correlate these structures with activity measurements using a panel of 13 different substrates. The catalytic activity of CD2 from both… Expand
Structural Basis of Catalysis and Inhibition of HDAC6 CD1, the Enigmatic Catalytic Domain of Histone Deacetylase 6.
TLDR
Examination of X-ray crystal structures of seven inhibitor complexes with wild-type, Y363F, and K330L HDAC6 CD1 establishes a foundation for understanding the structural basis ofHDAC6CD1 catalysis and inhibition, pointing to possible avenues for the development of HDAC 6 CD1-selective inhibitors. Expand
Binding of N8-Acetylspermidine Analogues to Histone Deacetylase 10 Reveals Molecular Strategies for Blocking Polyamine Deacetylation.
TLDR
X-ray crystal structures of zebrafish HDAC10 complexed with eight different analogues of N8-acetylspermidine reveal interesting geometric changes in the metal coordination polyhedron that accommodate inhibitor binding. Expand
Methods for the expression, purification, and crystallization of histone deacetylase 6-inhibitor complexes.
TLDR
The preparation, purification, and crystallization of zCD2-inhibitor complexes enable the rapid acquisition of structural data regarding optimal zinc-binding groups, capping groups, and linkers in the discovery of new and selective HDAC6 inhibitors. Expand
Structural Basis for the Selective Inhibition of HDAC10, the Cytosolic Polyamine Deacetylase.
TLDR
X-ray crystal structures of thisHDAC10 variant complexed with Tubastatin A and indole analogues bearing pendant tertiary amines reveal that inhibitors capable of hydrogen bonding with gatekeeper E274 exhibit high affinity and selectivity for HDAC10 over HDAC6 (the other class IIb isozyme), and reveal that the P(E,A)CE motif helix can shift by up to 2 Å to accommodate the binding of bulky inhibitors. Expand
Insights into structural features of HDAC1 and its selectivity inhibition elucidated by Molecular dynamic simulation and Molecular Docking
TLDR
It is found that the presence or absence of K+ not only impacted the structural flexibility of HDAC1, but also its molecular recognition, consistent with experimental findings, which could therefore be useful for further structure-based drug design studies addressing newHDAC1 inhibitors. Expand
Entropy as a Driver of Selectivity for Inhibitor Binding to Histone Deacetylase 6.
TLDR
High-resolution crystal structures of HDAC6 complexed with capless cycloalkyl hydroxamate inhibitors 1-4 are reported, revealing the chemical basis forHDAC6 selectivity and a promising lead for derivatization with capping groups that may further enhance its impressive 313-fold thermodynamic selectivity. Expand
Structure-activity relationship study of thiazolyl-hydroxamate derivatives as selective histone deacetylase 6 inhibitors.
TLDR
A new rationale for the design of HDAC6-selective inhibitors is suggested, based on the importance of the optimal aliphatic linker size, as well as the electronic substituent effect and rigidity of the aryl cap group. Expand
Exploring Structural Determinants of Inhibitor Affinity and Selectivity in Complexes with Histone Deacetylase 6.
TLDR
The X-ray crystal structures of five HDAC6-inhibitor complexes are presented that illuminate key molecular features of inhibitor linker and capping groups that facilitate and differentiate binding toHDAC6. Expand
Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors
TLDR
X-ray crystal structures of HDAC6-inhibitor complexes reveal molecular features responsible for the isozyme selectivity measured in inhibition assays, including an unusual monodentate hydroxamate-Zn2+ coordination mode as well as intermolecular interactions of bulky inhibitor substituents that will inform the design of HDac6-selective inhibitors with improved properties. Expand
Multicomponent synthesis, binding mode and structure-activity relationships of selective histone deacetylase 6 (HDAC6) inhibitors with bifurcated capping groups.
TLDR
The multicomponent synthesis and structure-activity relationships of a series of tetrazole-based HDAC6 inhibitors are presented and it is revealed that the steric complementarity of the bifurcated capping group of NR-160 to the L1 and L2 loop pockets may be responsible for itsHDAC6-selective inhibition. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 59 REFERENCES
Structure, mechanism, and inhibition of histone deacetylases and related metalloenzymes.
TLDR
Structural comparisons among HDACs and HDAC-related deacetylases reveal a conserved constellation of active site residues, suggesting a common mechanism for the metal-dependent hydrolysis of acetylated substrates. Expand
Structural studies of human histone deacetylase 8 and its site-specific variants complexed with substrate and inhibitors.
TLDR
These structures, along with those of the D101N, D101E, D 101A, and D101L variants, support the proposal that D101 is critical for the function of the L2 loop and illustrate ligand-induced conformational changes in the L1 loop that likely accompany substrate binding and catalysis. Expand
General Base-General Acid Catalysis in Human Histone Deacetylase 8.
TLDR
Enzymological and structural studies strongly suggest that H143 functions as a single general base-general acid catalyst, while H142 remains positively charged and serves as an electrostatic catalyst for transition state stabilization. Expand
Development of a histone deacetylase 6 inhibitor and its biological effects
TLDR
The HDAC6-selective inhibitor HPOB has therapeutic potential in combination therapy to enhance the potency of anticancer drugs. Expand
Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8–substrate complex
TLDR
The structure clarifies the role of active‐ site residues in the deacetylation reaction and substrate recognition and shows the unexpected role of a conserved residue at the active‐site rim, Asp 101, in positioning the substrate by directly interacting with the peptidic backbone and imposing a constrained cis‐conformation. Expand
Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation
TLDR
It is suggested that small molecules that selectively inhibit HDAC6-mediated α-tubulin deacetylation, a first example of which is tubacin, might have therapeutic applications as antimetastatic and antiangiogenic agents. Expand
Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors
The zinc-dependent mammalian histone deacetylase (HDAC) family comprises 11 enzymes, which have specific and critical functions in development and tissue homeostasis. Mounting evidence points to aExpand
Characterization of the two catalytic domains in histone deacetylase 6.
TLDR
The results indicate that the in vitro deacetylase activity of HDAC6 resides in the C-terminal second catalytic domain, yet the role towards substrate played by these two domains remains ambiguous. Expand
Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin.
TLDR
Interestingly, HDAC6, but not HDAC1 or HDAC4, was resistant to TPX and CHAP1, whereas TSA inhibited these HDACs to a similar extent, indicating that the structure of the cyclic tetrapeptide framework affects the target enzyme specificity. Expand
Two Catalytic Domains Are Required for Protein Deacetylation*
TLDR
It is demonstrated for the first time that the spatial arrangement of hdac domains is critical for in vivo deacetylation reaction and may provide a useful model for the development of novel HDAC inhibitors. Expand
...
1
2
3
4
5
...