Human HDAC7 Harbors a Class IIa Histone Deacetylase-specific Zinc Binding Motif and Cryptic Deacetylase Activity

Histone deacetylases (HDACs) are protein deacetylases that play a role in repression of gene transcription and are emerging targets in cancer therapy. Here, we characterize the structure and enzymatic activity of the catalytic domain of human HDAC7 (cdHDAC7). Although HDAC7 normally exists as part of a multiprotein complex, we show that cdHDAC7 has a low level of deacetylase activity which can be inhibited by known HDAC inhibitors. The crystal structures of human cdHDAC7 and its complexes with two hydroxamate inhibitors are the first structures of the catalytic domain of class IIa HDACs and demonstrate significant differences with previously reported class I and class IIb-like HDAC structures. We show that cdHDAC7 has an additional class IIa HDAC-specific zinc binding motif adjacent to the active site which is likely to participate in substrate recognition and protein-protein interaction and may provide a site for modulation of activity. Furthermore, a different active site topology results in modified catalytic properties and in an enlarged active site pocket. Our studies provide mechanistic insights into class IIa HDACs and facilitate the design of specific modulators. Histone deacetylases (HDACs) are protein deacetylases that play a role in repression of gene transcription and are emerging targets in cancer therapy. Here, we characterize the structure and enzymatic activity of the catalytic domain of human HDAC7 (cdHDAC7). Although HDAC7 normally exists as part of a multiprotein complex, we show that cdHDAC7 has a low level of deacetylase activity which can be inhibited by known HDAC inhibitors. The crystal structures of human cdHDAC7 and its complexes with two hydroxamate inhibitors are the first structures of the catalytic domain of class IIa HDACs and demonstrate significant differences with previously reported class I and class IIb-like HDAC structures. We show that cdHDAC7 has an additional class IIa HDAC-specific zinc binding motif adjacent to the active site which is likely to participate in substrate recognition and protein-protein interaction and may provide a site for modulation of activity. Furthermore, a different active site topology results in modified catalytic properties and in an enlarged active site pocket. Our studies provide mechanistic insights into class IIa HDACs and facilitate the design of specific modulators. The level of histone acetylation is regulated by the action of two classes of enzymes, histone acetyltransferases and histone deacetylases (HDACs). 3The abbreviations used are: HDAC, histone deacetylase; cdHDAC7, catalytic domain of human HDAC7; TSA, trichostatin A; SAHA, suberoylanilide hydroxamic acid; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; DTT, dithiothreitol. Histone acetyltransferases and HDACs are found in large multiprotein complexes, and recruitment of histone acetylase or deacetylase complexes by coactivators or corepressors is thought to cause a local change in the chromatin structure, resulting in either activation or repression of gene transcription (1Kao H.Y. Downes M. Ordentlich P. Evans R.M. Genes Dev. 2000; 14: 55-66PubMed Google Scholar). Humans have 18 HDACs and, based on their sequence similarity to yeast factors, they are grouped into four classes (class I–IV). Class II HDACs are homologous to yeast histone deacetylase HDA1 and have been implicated as global regulators of gene expression during cell differentiation and development (2Verdin E. Dequiedt F. Kasler H.G. Trends Genet. 2003; 19: 286-293Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar). In humans, class II HDACs are subdivided into classes IIa (HDAC4, HDAC5, HDAC7, and HDAC9) and IIb (HDAC6 and HDAC10). Class IIa HDACs contain two functionally important regions, a highly conserved C-terminal catalytic domain and an N-terminal extension that has no similarity with other proteins, mediates the signal-dependent shuttling between the nucleus and the cytoplasm, and harbors binding sites for transcriptional regulators (2Verdin E. Dequiedt F. Kasler H.G. Trends Genet. 2003; 19: 286-293Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar, 3Yang X.J. Gregoire S. Mol. Cell. Biol. 2005; 25: 2873-2884Crossref PubMed Scopus (357) Google Scholar). Class IIa HDACs interact with corepressors such as N-CoR (nuclear receptor corepressor) and the MEF2 (myocyte enhancer factor 2) family of transcription factors that is not only important for controlling gene expression in normal cellular programs like muscle differentiation, T-cell apoptosis, neuronal survival, and synaptic differentiation but has also been linked to cardiac hypertrophy, asthma, atherosclerosis, hypertension, and other pathological conditions (3Yang X.J. Gregoire S. Mol. Cell. Biol. 2005; 25: 2873-2884Crossref PubMed Scopus (357) Google Scholar, 4Gregoire S. Xiao L. Nie J. Zhang X. Xu M. Li J. Wong J. Seto E. Yang X.J. Mol. Cell. Biol. 2007; 27: 1280-1295Crossref PubMed Scopus (165) Google Scholar, 5Bertos N.R. Wang A.H. Yang X.J. Biochem. Cell Biol. 2001; 79: 243-252Crossref PubMed Scopus (243) Google Scholar). To date all four class IIa HDACs have been knocked out in mice, and the resulting abnormal phenotypes have been extensively characterized (6Vega R.B. Matsuda K. Oh J. Barbosa A.C. Yang X. Meadows E. McAnally J. Pomajzl C. Shelton J.M. Richardson J.A. Karsenty G. Olson E.N. Cell. 2004; 119: 555-566Abstract Full Text Full Text PDF PubMed Scopus (644) Google Scholar, 7Chang S. Young B.D. Li S. Qi X. Richardson J.A. Olson E.N. Cell. 2006; 126: 321-334Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar, 8Chang S. McKinsey T.A. Zhang C.L. Richardson J.A. Hill J.A. Olson E.N. Mol. Cell. Biol. 2004; 24: 8467-8476Crossref PubMed Scopus (495) Google Scholar, 9Zhang C.L. McKinsey T.A. Chang S. Antos C.L. Hill J.A. Olson E.N. Cell. 2002; 110: 479-488Abstract Full Text Full Text PDF PubMed Scopus (816) Google Scholar). HDAC7 for example, plays an important role in cardiovascular development and disease (7Chang S. Young B.D. Li S. Qi X. Richardson J.A. Olson E.N. Cell. 2006; 126: 321-334Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar). HDACs catalyze the deacetylation of lysine residues in the N-terminal tails of core histones. In addition to histones, nonhistone proteins may also serve as substrates (10Zhang Y. Li N. Caron C. Matthias G. Hess D. Khochbin S. Matthias P. EMBO J. 2003; 22: 1168-1179Crossref PubMed Scopus (574) Google Scholar, 11Hubbert C. Guardiola A. Shao R. Kawaguchi Y. Ito A. Nixon A. Yoshida M. Wang X.F. Yao T.P. Nature. 2002; 417: 455-458Crossref PubMed Scopus (1793) Google Scholar). The currently accepted catalytic mechanism of HDACs has features of both metallo- and serine proteases. In a first step a tetrahedral oxyanion intermediate is formed after the nucleophilic attack of a zinc-activated water molecule on the carbonyl carbon of the substrate acetyl group. The negative charge of the tetrahedral oxyanion intermediate is stabilized by interactions with the zinc and the side chain of an active site tyrosine. The reaction is completed by the transfer of a proton to the scissile nitrogen, yielding the acetate and lysine products (12Finnin M.S. Donigian J.R. Cohen A. Richon V.M. Rifkind R.A. Marks P.A. Breslow R. Pavletich N.P. Nature. 1999; 401: 188-193Crossref PubMed Scopus (1500) Google Scholar, 13Somoza J.R. Skene R.J. Katz B.A. Mol C. Ho J.D. Jennings A.J. Luong C. Arvai A. Buggy J.J. Chi E. Tang J. Sang B.C. Verner E. Wynands R. Leahy E.M. Dougan D.R. Snell G. Navre M. Knuth M.W. Swanson R.V. McRee D.E. Tari L.W. Structure. 2004; 12: 1325-1334Abstract Full Text Full Text PDF PubMed Scopus (607) Google Scholar, 14Nielsen T.K. Hildmann C. Dickmanns A. A. R. J. Mol. Biol. 2005; PubMed Scopus Google Scholar, A. C. P. P. M. A. R. C. S. EMBO 2007; PubMed Scopus Google Scholar). The activity of the class IIa HDACs is regulated gene shuttling that is on their and binding of proteins, and recruitment of (2Verdin E. Dequiedt F. Kasler H.G. Trends Genet. 2003; 19: 286-293Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar, 3Yang X.J. Gregoire S. Mol. Cell. Biol. 2005; 25: 2873-2884Crossref PubMed Scopus (357) Google Scholar). In the enzymatic activity of class IIa HDACs is on a multiprotein and for and Dequiedt F. E. Mol. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, Dequiedt F. M. E. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). HDACs are to be the targets in development for cancer 2005; PubMed Scopus Google Scholar, S. 2006; PubMed Scopus Google and like suberoylanilide hydroxamic are in P.A. 2007; PubMed Scopus Google Scholar). of the HDAC inhibitors their in and 2006; PubMed Scopus Google Scholar). only a are emerging as inhibitors of class I class II and are to HDACs that to the class S. 2006; PubMed Scopus Google Scholar). HDAC structures in with inhibitors a for HDAC The of a binding which the active site zinc and the enzymatic a which the substrate and the enzymatic and a which with the of the binding S. 2006; PubMed Scopus Google Scholar, T.A. S. J. 2003; PubMed Scopus Google Scholar). To date the crystal structures of human and a HDAC both class I and the class IIb have been reported (12Finnin M.S. Donigian J.R. Cohen A. Richon V.M. Rifkind R.A. Marks P.A. Breslow R. Pavletich N.P. Nature. 1999; 401: 188-193Crossref PubMed Scopus (1500) Google Scholar, 13Somoza J.R. Skene R.J. Katz B.A. Mol C. Ho J.D. Jennings A.J. Luong C. Arvai A. Buggy J.J. Chi E. Tang J. Sang B.C. Verner E. Wynands R. Leahy E.M. Dougan D.R. Snell G. Navre M. Knuth M.W. Swanson R.V. McRee D.E. Tari L.W. Structure. 2004; 12: 1325-1334Abstract Full Text Full Text PDF PubMed Scopus (607) Google Scholar, 14Nielsen T.K. Hildmann C. Dickmanns A. A. R. J. Mol. Biol. 2005; PubMed Scopus Google Scholar, A. C. P. P. M. A. R. C. S. EMBO 2007; PubMed Scopus Google Scholar, A. C. G. M. D. P. C. R. P. C. S. S. A. 2004; PubMed Scopus Google Scholar, M. Kasler McKinsey T.A. Olson E.N. E. J. Biol. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, T.K. Hildmann C. D. D. A. R. Biol. 2007; PubMed Scopus Google Scholar). is no for class II and class IIa To provide into the structure and of we the crystal structure of the catalytic domain of human HDAC7 and two structures. The crystal structure of cdHDAC7 is the first structure of the catalytic domain of a class IIa HDAC, significant differences with previously reported human and class I and class IIb-like HDAC structures. cdHDAC7 has a zinc binding motif adjacent to the active which is conserved in class IIa HDACs and likely in substrate recognition and protein-protein cdHDAC7 also has a active site topology resulting in catalytic properties and in an enlarged active site pocket. Our cdHDAC7 studies provide mechanistic insights into class IIa HDACs and may the design of HDAC modulators. HDAC inhibitors as in other of the and of of cdHDAC7 by the and into a modified cdHDAC7 and in in in the of to an of to and by in CHAPS, DTT, and and by a The two an on a with and on a The with of CHAPS, and and the protein with to cdHDAC7 and and The protein to by after the with cdHDAC7 with a of to The protein to the in of and binding by the in of proteins in the of as previously M. A. R. C. R. B.D. P. M. J. S. A. 2006; PubMed Scopus Google Scholar). of protein to a of in of a a of by the of the with a The in a of to a of the of in that for and to the by The resulting of of resulting as the deacetylase activity the to the The in after a To and cdHDAC7 different of substrate to and to to be to the low level of activity of the the cdHDAC7 of and of and reaction in HDAC activity also in the of inhibitors SAHA, TSA, and to of cdHDAC7 the by of the protein DTT, and with of the cdHDAC7 with a of the hydroxamate no in the cdHDAC7 a water molecule the catalytic zinc as in the structure of the protein A. (12Finnin M.S. Donigian J.R. Cohen A. Richon V.M. Rifkind R.A. Marks P.A. Breslow R. Pavletich N.P. Nature. 1999; 401: 188-193Crossref PubMed Scopus (1500) Google Scholar, E. E. R. Zhang K. R. A. G. R. M. P. J. J. M. J. 2003; PubMed Scopus Google To the with the and to be in the during crystal The by to cdHDAC7 by to protein by to in a and the crystal in nitrogen, the crystal in a of and and for and cdHDAC7 and of the PubMed Scopus Google Scholar). are reported in and cdHDAC7 structures by the A.J. R.J. Biol. 2005; PubMed Scopus Google Scholar). the structure of the of class IIb protein as a T.K. Hildmann C. Dickmanns A. A. R. J. Mol. Biol. 2005; PubMed Scopus Google and for structures the of used as a of the with D. Biol. PubMed Scopus Google Scholar). used for and P. K. D. Biol. 2004; PubMed Scopus Google Scholar). on structure are in with J.D. 22: PubMed Scopus Google Scholar). out the and out with J. M. R. 2003; PubMed Scopus Google Scholar). of an by R. M. J. Mol. Biol. PubMed Scopus Google Scholar). The to by a in the of the active site The level with the catalytic The water molecule a with and the have been into the as and and of we the and catalytic activity of a human class IIa HDAC a activity that has been for other class II HDACs X. Marks P.A. Rifkind R.A. Richon V.M. S. A. 2001; PubMed Scopus Google Scholar, N. 2004; PubMed Scopus Google Scholar, A. C. M. P. P. S. P. A. R. C. P. S. A. 2007; PubMed Scopus Google we the for cdHDAC7 The for the substrate is in the as of other substrates for HDACs C. D. D. R. A. J. L. S. T.K. R. A. J. 2006; PubMed Scopus Google Scholar, D. Hildmann C. S. A. Biochem. 2007; PubMed Scopus Google Scholar). cdHDAC7 the level of catalytic activity as HDAC C. D. D. R. A. J. L. S. T.K. R. A. J. 2006; PubMed Scopus Google which is that of the class IIb-like HDAC C. D. D. R. A. J. L. S. T.K. R. A. J. 2006; PubMed Scopus Google for human cdHDAC7 activity of cdHDAC7 and its the cdHDAC7 in the HDAC the cdHDAC7 of and of and in a To inhibitors of human HDAC7, we first the binding of a of known HDAC inhibitors by the in of cdHDAC7 in the of cdHDAC7 significant binding to hydroxamate inhibitors such as TSA, and binding found for inhibitors and and chain and The results are with the for the class HDAC C. D. D. R. A. J. L. S. T.K. R. A. J. 2006; PubMed Scopus Google of known HDAC inhibitors on of cdHDAC7 of different HDAC inhibitors on cdHDAC7 by the in of proteins in the of inhibitors is are and the structures and for are in are and the structures and for are in are and the structures and for are in are and the structures and for are in are and the structures and for are in in a To the and of hydroxamate inhibitors on human class IIa we first activity in the of of not hydroxamic the inhibitors of deacetylase activity. for the inhibitors The for cdHDAC7 deacetylase activity the HDAC with an of have been reported for the class IIb-like HDAC C. M. R. D. D. C. P. A. J. 2004; PubMed Scopus Google human class I HDACs and and the A. of (12Finnin M.S. Donigian J.R. Cohen A. Richon V.M. Rifkind R.A. Marks P.A. Breslow R. Pavletich N.P. Nature. 1999; 401: 188-193Crossref PubMed Scopus (1500) Google Scholar, E. E. R. Zhang K. R. A. G. R. M. P. J. J. M. J. 2003; PubMed Scopus Google of known HDAC inhibitors on activity of cdHDAC7 The for hydroxamate different different in a cdHDAC7 a Class IIa HDAC-specific the mechanism of and of HDAC7, we the crystal structure of its catalytic domain as as two complexes with the hydroxamate inhibitors and In all cdHDAC7 crystal structures are protein in the of and in a domain with an The of cdHDAC7 residues In the structure the catalytic zinc to the side of and and water molecule residues that are in binding the catalytic zinc are highly conserved in the class I and II HDACs are cdHDAC7 and are also conserved in human and in the protein T.K. Hildmann C. Dickmanns A. A. R. J. Mol. Biol. 2005; PubMed Scopus Google Scholar, A. C. G. M. D. P. C. R. P. C. S. S. A. 2004; PubMed Scopus Google Scholar). The of cdHDAC7 is to other reported HDAC structures. The of the structures of human cdHDAC7 and class II with a of The of the structures of human and protein A. both class I with a of and on human cdHDAC7, The is found in the active site In cdHDAC7, the of and its results in a of the active differences are in the and its in the and and residues between and and residues that in class I and class II HDACs and, are likely to be in of substrate binding The of cdHDAC7 is a zinc binding motif to class IIa HDACs (HDAC4, HDAC5, HDAC7, and motif is formed by a class IIa HDAC-specific a by two and and the between and The zinc the side of and residues that are conserved in class IIa HDACs with a of and The which is the active site is in to the of the in structures and The of the zinc binding to as the are motif a to the of the active site the motif a which may a site for of additional factors proteins and and To a substrate interact with both the active site and the we used to an to that of the structure A. C. P. P. M. A. R. C. S. EMBO 2007; PubMed Scopus Google Scholar). In the the in the by the class and and its the active site The with cdHDAC7, a between the of the lysine to the side chain of a to the substrate structure A. C. P. P. M. A. R. C. S. EMBO 2007; PubMed Scopus Google Scholar). The of the lysine in a and to cdHDAC7, that is a motif for HDAC7 we that is currently no that is a substrate for HDAC7, and studies in of HDAC7 substrates are a is the class IIa HDAC-specific two a and a which substrate and binding of the class IIa HDAC-specific motif may be in substrate of activity. of of both the and the structures for the but and for the hydroxamate of the inhibitors and The hydroxamate with the side of two active site and the interactions of the water molecule in the active site of and The of the the water which found in the active site of the hydroxamate of the a with the catalytic zinc only the the in the HDAC structures reported the and the carbonyl of the the zinc The of and in the structures the different topology of the active in the other HDAC structures a in protein in A. and in human the carbonyl of the hydroxamate cdHDAC7 active site tyrosine. In cdHDAC7, the is found the active site the active site is conserved the and class I and IIb the is found in class IIa HDACs a of the different topology of the active site the the hydroxamate carbonyl is the zinc and a with a water which is in the other HDAC structures but found in all cdHDAC7 structures The water molecule is the carbonyl of the as is the in human the side chain of which are the of the and change to the are no significant binding also of for the protein that of the active site into deacetylase activity with an lysine K. D. Hildmann C. R. D. A. A. Biochem. J. 2007; 401: PubMed Scopus Google Scholar). To the role of the in cdHDAC7 we and and for deacetylase activity. cdHDAC7 active the with the of to the cdHDAC7 is active cdHDAC7 and also active class I HDAC with a substrate C. D. D. R. A. J. L. S. T.K. R. A. J. 2006; PubMed Scopus Google Scholar, D. Hildmann C. S. A. Biochem. 2007; PubMed Scopus Google Scholar, K. D. Hildmann C. R. D. A. A. Biochem. J. 2007; 401: PubMed Scopus Google Scholar). the of the in cdHDAC7 may the low level of deacetylase activity found for Our the important role of in We that by the tetrahedral oxyanion intermediate as for other that the side chain is the active the side chain in structures. in deacetylase activity is also for the and the are for cdHDAC7 and all cdHDAC7 of the active site to the substrate Our of the show that of the inhibitors are for the with cdHDAC7 the role of the side chain of the in binding and the oxyanion intermediate during HDAC7 previously reported to have enzymatic activity only to the Dequiedt F. E. Mol. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, Dequiedt F. M. E. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). not the HDAC activity to HDAC7 or the HDAC7 not be a HDAC in the of the but serve to active complexes that contain In the provide a between active and In the HDAC7 only in the of (2Verdin E. Dequiedt F. Kasler H.G. Trends Genet. 2003; 19: 286-293Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar, Dequiedt F. E. Mol. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). class IIa HDAC, to have deacetylase but its activity to the expression that an factor is for deacetylase activity A.H. N.R. M. N. M. J. J. Yang X.J. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar). and other class IIa HDACs reported to only transcription by the active and transcription factors of HDAC activity Dequiedt F. E. Mol. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, Dequiedt F. M. E. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). protein and as The in show that the and catalytic domain of the human class IIa HDAC, cdHDAC7, has an low level of deacetylase activity in the of which can be inhibited by known HDAC inhibitors such as the hydroxamic In to A. C. M. P. P. S. P. A. R. C. P. S. A. 2007; PubMed Scopus Google also that the catalytic domain of class IIa HDACs have but catalytic activity on core histones. they also a of for class IIa HDACs of the active site into the of in A. C. M. P. P. S. P. A. R. C. P. S. A. 2007; PubMed Scopus Google Scholar). the substrate and of cdHDAC7 are with other HDACs C. D. D. R. A. J. L. S. T.K. R. A. J. 2006; PubMed Scopus Google the catalytic of cdHDAC7 is be to the in catalytic properties of HDAC7 and other class IIa their substrates are and has been that HDACs show different catalytic with different substrate A. C. M. P. P. S. P. A. R. C. P. S. A. 2007; PubMed Scopus Google Scholar, D. Hildmann C. S. A. Biochem. 2007; PubMed Scopus Google Scholar, C. M. R. D. D. C. P. A. J. 2004; PubMed Scopus Google Scholar, D. D. Hildmann C. A. Biochem. 2004; PubMed Scopus Google Scholar). the other the that the side chain of the cdHDAC7 active site also the activity of cdHDAC7 in is to to the of the substrate acetyl and the of the tetrahedral oxyanion intermediate during as for the of other is that binding of a protein substrate the side chain of the the catalytic site and acetyl of the substrate Our the of cdHDAC7 to an of the side chain of a the catalytic as as for inhibitors with for the to to are an to the active site and a side chain of to the reaction intermediate or to or water that can to the In the of the and of cdHDAC7 as as the structure with likely (2Verdin E. Dequiedt F. Kasler H.G. Trends Genet. 2003; 19: 286-293Abstract Full Text Full Text PDF PubMed Scopus (547) Google that class II HDAC enzymatic activity may be by of its interactions with other proteins, that the only active after in an multiprotein S. L. G. 2001; PubMed Scopus Google that substrate on that complexes with and that binding can the of enzymatic substrate D. Hildmann C. S. A. Biochem. 2007; PubMed Scopus Google Scholar). Our of cdHDAC7 a mechanism for modulation of and activity of class IIa HDACs a multiprotein The class IIa HDAC-specific motif a in the of the catalytic site and and a protein binding and and protein binding is to but the active site and may a substrate recruitment or a site for protein-protein for the class IIa HDACs and M. R. PubMed Scopus Google as as sequence that residues the are conserved the class IIa HDAC family also is likely that the the recruitment for to its to the active site and binding binding of proteins may HDAC activity substrate in cdHDAC7 is the active site and the class IIa HDAC-specific binding is that a multiprotein the active of the oxyanion the HDAC activity The that of have a HDAC activity the may also class IIa HDAC activity Class IIa HDACs show and has been for HDAC5, and HDAC7 H.Y. A. C. Khochbin S. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, T.A. Zhang C.L. J. Olson E.N. Nature. 2000; PubMed Scopus Google Scholar). In the class IIa HDACs as transcriptional T-cell receptor and HDACs into the substrates for class IIa HDACs are not is that deacetylation of substrates other be regulated binding pocket. we that the class IIa HDACs likely the motif to activity and substrate and to to has been that inhibitors specific to class I HDACs may be and of class II HDACs to be of (3Yang X.J. Gregoire S. Mol. Cell. Biol. 2005; 25: 2873-2884Crossref PubMed Scopus (357) Google Scholar). The crystal structure of human cdHDAC7 in a for the development of such HDAC modulators. a of the the active site of cdHDAC7 is for the development of highly specific class IIa HDAC the between and may binding of with that can be in for the development of specific HDAC be to the of the for interaction with residues of the motif as as the protein binding adjacent to the active The that cdHDAC7 activity can be by of the the catalytic site is by of cdHDAC7 all catalytic with In studies provide the first of the catalytic domain of a class IIa HDAC and for specific features a zinc binding motif that is likely to be in substrate binding protein-protein interactions and may provide a site for modulation of activity and a active site topology resulting in a catalytic activity and in an enlarged active site pocket. structures may the design of specific class IIa HDAC modulators. of class II HDACs be to insights into the of human and to HDAC with We J. for with

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