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ABSTRACT: In plants oxylipins regulate developmental processes and defence responses. The first specific step in the biosynthesis of the cyclopentanone class of oxylipins is catalyzed by allene oxide cyclase (AOC) that forms cis(+)-12-oxo phytodienoic acid. The moss Physcomitrella patens has two AOCs (PpAOC1 + 2) with different substrate specificities for C18 and C20-derived substrates, respectively. To better understand AOC's catalytic mechanism and to elucidate the structural properties that explain the differences in substrate specificity, we solved and analyzed the crystal structures of 36 monomers of both apo and ligand complexes of PpAOC1 and 2. From these data we propose the following intermediates in AOC catalysis: (i) a resting state of the apo enzyme with a closed conformation, (ii) a first shallow binding mode, followed by (iii) a tight binding of the substrate accompanied by conformational changes in the binding pocket, and (iv) initiation of the catalytic cycle by opening of the epoxide ring. As expected, the substrate dihydro analogue cis-12,13-epoxyoctadecadienoic acid did not cyclize in the presence of PpAOC1, however, when bound to the enzyme it underwent isomerization into the corresponding trans-epoxide. By comparing complex structures of the C18 substrate analogue with in silico modeling of the C20 substrate analogue bound to the enzyme allowed us to identify three major molecular determinants responsible for the different substrate specificities, i.e. larger active site diameter and an elongated cavity of PpAOC2 and two non-identical residues at the entrance of the active site.
Plant physiology 09/2012; · 6.53 Impact Factor
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ABSTRACT: Nucleotide sugars and the enzymes that are responsible for their synthesis are indispensable for the production of complex carbohydrates and, thus, for elaboration of a protective cellular coat for many organisms such as the protozoan parasite Leishmania. These activated sugars are synthesized de novo or derived from salvaged monosaccharides. In addition to UDP-glucose (UDP-Glc) pyrophosphorylase, which catalyzes the formation of UDP-Glc from substrates UTP and glucose-1-phosphate, Leishmania major and plants express a UDP-sugar pyrophosphorylase (USP) that exhibits broad substrate specificity in vitro. The enzyme, likely involved in monosaccharide salvage, preferentially generates UDP-Glc and UDP-galactose, but it may also activate other hexose- or pentose-1-phosphates such as galacturonic acid-1-phosphate or arabinose-1-phosphate. In order to gain insight into structural features governing the differences in substrate specificity, we determined the crystal structure of the L. major USP in the APO-, UTP-, and UDP-sugar-bound conformations. The overall tripartite structure of USP exhibits a significant structural homology to other nucleotidyldiphosphate-glucose pyrophosphorylases. The obtained USP structures reveal the structural rearrangements occurring during the stepwise binding process of the substrates. Moreover, the different product complexes explain the broad substrate specificity of USP, which is enabled by structural changes in the sugar binding region of the active site.
Journal of Molecular Biology 11/2010; 405(2):461-78. · 4.00 Impact Factor
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ABSTRACT: Mass spectrometry allows the elucidation of molecular details of the interaction domains of the individual components in macromolecular complexes subsequent to cross-linking of the individual components. Here, we applied chemical and UV cross-linking combined with tandem mass-spectrometric analysis to identify contact sites of the nuclear import adaptor snurportin 1 to the small ribonucleoprotein particle U1 snRNP in addition to the known interaction of m(3)G cap and snurportin 1. We were able to define previously unknown sites of protein-protein and protein-RNA interactions on the molecular level within U1 snRNP. We show that snurportin 1 interacts with its central m(3)G-cap-binding domain with Sm proteins and with its extreme C-terminus with stem-loop III of U1 snRNA. The crosslinking data support the idea of a larger interaction area between snurportin 1 and U snRNPs and the contact sites identified prove useful for modeling the spatial arrangement of snurportin 1 domains when bound to U1 snRNP. Moreover, this suggests a functional nuclear import complex that assembles around the m(3)G cap and the Sm proteins only when the Sm proteins are bound and arranged in the proper orientation to the cognate Sm site in U snRNA.
Nucleic Acids Research 09/2010; 38(16):5581-93. · 8.03 Impact Factor
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ABSTRACT: The reliable repair of pre-mutagenic U/G mismatches that originated from hydrolytic cytosine deamination is crucial for the maintenance of the correct genomic information. In most organisms, any uracil base in DNA is attacked by uracil DNA glycosylases (UDGs), but at least in Methanothermobacter thermautotrophicus DeltaH, an alternative strategy has evolved. The exonuclease III homologue Mth212 from the thermophilic archaeon M. thermautotrophicus DeltaH exhibits a DNA uridine endonuclease activity in addition to the apyrimidinic/apurinic site endonuclease and 3'-->5'exonuclease functions. Mth212 alone compensates for the lack of a UDG in a single-step reaction thus substituting the two-step pathway that requires the consecutive action of UDG and apyrimidinic/apurinic site endonuclease. In order to gain deeper insight into the structural basis required for the specific uridine recognition by Mth212, we have characterized the enzyme by means of X-ray crystallography. Structures of Mth212 wild-type or mutant proteins either alone or in complex with DNA substrates and products have been determined to a resolution of up to 1.2 A, suggesting key residues for the uridine endonuclease activity. The insertion of the side chain of Arg209 into the DNA helical base stack resembles interactions observed in human UDG and seems to be crucial for the uridine recognition. In addition, Ser171, Asn153, and Lys125 in the substrate binding pocket appear to have important functions in the discrimination of aberrant uridine against naturally occurring thymidine and cytosine residues in double-stranded DNA.
Journal of Molecular Biology 04/2010; 399(4):604-17. · 4.00 Impact Factor
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ABSTRACT: An alpha-2,8-linked polysialic acid (polySia) capsule confers immune tolerance to neuroinvasive, pathogenic prokaryotes such as Escherichia coli K1 and Neisseria meningitidis and supports host infection by means of molecular mimicry. Bacteriophages of the K1 family, infecting E. coli K1, specifically recognize and degrade this polySia capsule utilizing tailspike endosialidases. While the crystal structure for the catalytic domain of the endosialidase of bacteriophage K1F (endoNF) has been solved, there is yet no structural information on the mode of polySia binding and cleavage available. The crystal structure of activity deficient active-site mutants of the homotrimeric endoNF cocrystallized with oligomeric sialic acid identified three independent polySia binding sites in each endoNF monomer. The bound oligomeric sialic acid displays distinct conformations at each site. In the active site, a Sia(3) molecule is bound in an extended conformation representing the enzyme-product complex. Structural and biochemical data supported by molecular modeling enable to propose a reaction mechanism for polySia cleavage by endoNF.
Journal of Molecular Biology 03/2010; 397(1):341-51. · 4.00 Impact Factor
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ABSTRACT: Protein folding is often mediated by molecular chaperones. Recently, a novel class of intramolecular chaperones has been identified in tailspike proteins of evolutionarily distant viruses, which require a C-terminal chaperone for correct folding. The highly homologous chaperone domains are interchangeable between pre-proteins and release themselves after protein folding. Here we report the crystal structures of two intramolecular chaperone domains in either the released or the pre-cleaved form, revealing the role of the chaperone domain in the formation of a triple-beta-helix fold. Tentacle-like protrusions enclose the polypeptide chains of the pre-protein during the folding process. After the assembly, a sensory mechanism for correctly folded beta-helices triggers a serine-lysine catalytic dyad to autoproteolytically release the mature protein. Sequence analysis shows a conservation of the intramolecular chaperones in functionally unrelated proteins sharing beta-helices as a common structural motif.
Nature Structural & Molecular Biology 02/2010; 17(2):210-5. · 12.71 Impact Factor
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ABSTRACT: The lysosomal 66.3 kDa protein from mouse is a soluble, mannose 6-phosphate containing protein of so far unknown function. It is synthesized as a glycosylated 75 kDa precursor that undergoes limited proteolysis leading to a 28 kDa N- and a 40 kDa C-terminal fragment.
In order to gain insight into the function and the post-translational maturation process of the glycosylated 66.3 kDa protein, three crystal structures were determined that represent different maturation states. These structures demonstrate that the 28 kDa and 40 kDa fragment which have been derived by a proteolytic cleavage remain associated. Mass spectrometric analysis confirmed the subsequent trimming of the C-terminus of the 28 kDa fragment making a large pocket accessible, at the bottom of which the putative active site is located. The crystal structures reveal a significant similarity of the 66.3 kDa protein to several bacterial hydrolases. The core alphabetabetaalpha sandwich fold and a cysteine residue at the N-terminus of the 40 kDa fragment (C249) classify the 66.3 kDa protein as a member of the structurally defined N-terminal nucleophile (Ntn) hydrolase superfamily.
Due to the close resemblance of the 66.3 kDa protein to members of the Ntn hydrolase superfamily a hydrolytic activity on substrates containing a non-peptide amide bond seems reasonable. The structural homology which comprises both the overall fold and essential active site residues also implies an autocatalytic maturation process of the lysosomal 66.3 kDa protein. Upon the proteolytic cleavage between S248 and C249, a deep pocket becomes solvent accessible, which harbors the putative active site of the 66.3 kDa protein.
BMC Structural Biology 09/2009; 9:56. · 2.48 Impact Factor
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Melanie Oschlies, Achim Dickmanns,
Thomas Haselhorst,
Wiebke Schaper,
Katharina Stummeyer,
Joe Tiralongo,
Birgit Weinhold,
Rita Gerardy-Schahn,
Mark von Itzstein,
Ralf Ficner,
Anja-K Münster-Kühnel
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ABSTRACT: The biosynthesis of sialic acid-containing glycoconjugates is crucial for the development of vertebrate life. Cytidine monophosphate-sialic acid synthetase (CSS) catalyzes the metabolic activation of sialic acids. In vertebrates, the enzyme is chimeric, with the N-terminal domain harboring the synthetase activity. The function of the highly conserved C-terminal domain (CSS-CT) is unknown. To shed light on its biological function, we solved the X-ray structure of murine CSS-CT to 1.9 A resolution. CSS-CT is a stable shamrock-like tetramer that superimposes well with phosphatases of the haloacid dehalogenase superfamily. However, a region found exclusively in vertebrate CSS-CT appears to block the active-site entrance. Accordingly, no phosphatase activity was observed in vitro, which points toward a nonenzymatic function of CSS-CT. A computational three-dimensional model of full-length CSS, in combination with in vitro oligomerization studies, provides evidence that CSS-CT serves as a platform for the quaternary organization governing the kinetic properties of the physiologically active enzyme as demonstrated in kinetic studies.
Journal of Molecular Biology 09/2009; 393(1):83-97. · 4.00 Impact Factor
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ABSTRACT: Methyltransferases play an important role in the post-transcriptional maturation of most ribonucleic acids. The modification of spliceosomal UsnRNAs includes N2-dimethylation of the m(7)G cap catalyzed by trimethylguanosine synthase 1 (TGS1). This 5'-cap hypermethylation occurs during the biogenesis of UsnRNPs as it initiates the m(3)G cap-dependent nuclear import of UsnRNPs. The conserved methyltransferase domain of human TGS1 has been purified, crystallized and the crystal structure of this domain with bound substrate m(7)GpppA was solved by means of multiple-wavelength anomalous dispersion. Crystal structure analysis revealed that m(7)GpppA binds via its adenosine moiety to the structurally conserved adenosylmethionine-binding pocket, while the m(7) guanosine remains unbound. This unexpected binding only occurs in the absence of AdoMet and suggests an incomplete binding pocket for the m(7)G cap which is caused by the N-terminal truncation of the protein. These structural data are consistent with the finding that the crystallized fragment of human TGS1 is catalytically inactive, while a fragment that is 17 amino acids longer exhibits activity.
Acta crystallographica. Section D, Biological crystallography 05/2009; 65(Pt 4):332-8. · 12.67 Impact Factor
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ABSTRACT: The 5'-cap of spliceosomal small nuclear RNAs, some small nucleolar RNAs and of telomerase RNA was found to be hypermethylated in vivo. The Trimethylguanosine Synthase 1 (TGS1) mediates this conversion of the 7-methylguanosine-cap to the 2,2,7-trimethylguanosine (m(3)G)-cap during maturation of the RNPs. For mammalian UsnRNAs the generated m(2,2,7)G-cap is one part of a bipartite import signal mediating the transport of the UsnRNP-core complex into the nucleus. In order to understand the structural organization of human TGS1 as well as substrate binding and recognition we solved the crystal structure of the active TGS1 methyltransferase domain containing both, the minimal substrate m(7)GTP and the reaction product S-adenosyl-L-homocysteine (AdoHcy). The methyltransferase of human TGS1 harbors the canonical class 1 methyltransferase fold as well as an unique N-terminal, alpha-helical domain of 40 amino acids, which is essential for m(7)G-cap binding and catalysis. The crystal structure of the substrate bound methyltransferase domain as well as mutagenesis studies provide insight into the catalytic mechanism of TGS1.
Nucleic Acids Research 05/2009; 37(12):3865-77. · 8.03 Impact Factor
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ABSTRACT: CRM1 mediates nuclear export of numerous unrelated cargoes, which may carry a short leucine-rich nuclear export signal or export signatures that include folded domains. How CRM1 recognizes such a variety of cargoes has been unknown up to this point. Here we present the crystal structure of the SPN1.CRM1.RanGTP export complex at 2.5 angstrom resolution (where SPN1 is snurportin1 and RanGTP is guanosine 5' triphosphate-bound Ran). SPN1 is a nuclear import adapter for cytoplasmically assembled, m(3)G-capped spliceosomal U snRNPs (small nuclear ribonucleoproteins). The structure shows how CRM1 can specifically return the cargo-free form of SPN1 to the cytoplasm. The extensive contact area includes five hydrophobic residues at the SPN1 amino terminus that dock into a hydrophobic cleft of CRM1, as well as numerous hydrophilic contacts of CRM1 to m(3)G cap-binding domain and carboxyl-terminal residues of SPN1. The structure suggests that RanGTP promotes cargo-binding to CRM1 solely through long-range conformational changes in the exportin.
Science 05/2009; 324(5930):1087-91. · 31.20 Impact Factor
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ABSTRACT: The 66.3 kDa protein from mouse is a soluble protein of the lysosomal matrix. It is synthesized as a glycosylated 75 kDa preproprotein which is further processed into 28 and 40 kDa fragments. Despite bioinformatics approaches and molecular characterization of the 66.3 kDa protein, the mode of its maturation as well as its physiological function remained unknown. Therefore, it was decided to tackle this question by means of X-ray crystallography. After expression in a human fibrosarcoma cell line, the C-terminally His-tagged single-chain 66.3 kDa variant and the double-chain form consisting of a 28 kDa fragment and a 40 kDa fragment were purified to homogeneity but could not be separated during the purification procedure. This mixture was therefore used for crystallization. Single crystals were obtained and the structure of the 66.3 kDa protein was solved by means of sulfur SAD phasing using data collected at a wavelength of 1.9 A on the BESSY beamline BL14.2 of Freie Universität Berlin. Based on the anomalous signal, a 22-atom substructure comprising 21 intrinsic S atoms and one Xe atom with very low occupancy was found and refined at a resolution of 2.4 A using the programs SHELXC/D and SHARP. Density modification using SOLOMON and DM resulted in a high-quality electron-density map, enabling automatic model building with ARP/wARP. The initial model contained 85% of the amino-acid residues expected to be present in the asymmetric unit of the crystal. Subsequently, the model was completed and refined to an R(free) factor of 19.8%. The contribution of the single Xe atom to the anomalous signal was analyzed in comparison to that of the S atoms and was found to be negligible. This work should encourage the use of the weak anomalous scattering of intrinsic S atoms in SAD phasing, especially for proteins, which require both expensive and time-consuming expression and purification procedures, preventing extensive screening of heavy-atom crystal soaks.
Acta crystallographica. Section D, Biological crystallography 04/2009; 65(Pt 3):220-8. · 12.67 Impact Factor
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ABSTRACT: Ynm3 is the only budding yeast protein possessing a combination of serine protease and postsynaptic density 95/disc-large/zona occludens domains, a defining feature of the high temperature requirement A (HtrA) protein family. The bacterial HtrA/DegP is involved in protective stress response to aid survival at higher temperatures. The role of mammalian mitochondrial HtrA2/Omi in protein quality control is unclear, although loss of its protease activity results in susceptibility toward Parkinson's disease, in which mitochondrial dysfunction and impairment of protein folding and degradation are key pathogenetic features. We studied the role of the budding yeast HtrA, Ynm3, with respect to unfolding stresses. Similar to Escherichia coli DegP, we find that Ynm3 is a dual chaperone-protease. Its proteolytic activity is crucial for cell survival at higher temperature. Ynm3 also exhibits strong general chaperone activity, a novel finding for a eukaryotic HtrA member. We propose that the chaperone activity of Ynm3 may be important to improve the efficiency of proteolysis of aberrant proteins by averting the formation of nonproductive toxic aggregates and presenting them in a soluble state to its protease domain. Suppression studies with Deltaynm3 led to the discovery of chaperone activity in a nucleolar peptidyl-prolyl cis-trans isomerase, Fpr3, which could partly relieve the heat sensitivity of Deltaynm3.
Molecular biology of the cell 11/2008; 20(1):68-77. · 5.98 Impact Factor
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ABSTRACT: Poly(A)-specific ribonuclease (PARN) is a processive 3'-exoribonuclease involved in the decay of eukaryotic mRNAs. Interestingly, PARN interacts not only with the 3' end of the mRNA but also with its 5' end as PARN contains an RRM domain that specifically binds both the poly(A) tail and the 7-methylguanosine (m(7)G) cap. The interaction of PARN with the 5' cap of mRNAs stimulates the deadenylation activity and enhances the processivity of this reaction. We have determined the crystal structure of the PARN-RRM domain with a bound m(7)G triphosphate nucleotide, revealing a novel binding mode for the m(7)G cap. The structure of the m(7)G binding pocket is located outside of the canonical RNA-binding surface of the RRM domain and differs significantly from that of other m(7)G-cap-binding proteins. The crystal structure also shows a remarkable conformational flexibility of the RRM domain, leading to a perfect exchange of two alpha-helices with an adjacent protein molecule in the crystal lattice.
Journal of Molecular Biology 08/2008; 382(4):827-34. · 4.00 Impact Factor
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Stefan Schäfer,
Laura Saunders,
Elena Eliseeva,
Alfredo Velena,
Mira Jung,
Andreas Schwienhorst,
Anja Strasser, Achim Dickmanns,
Ralf Ficner,
Sonja Schlimme,
Wolfgang Sippl,
Eric Verdin,
Manfred Jung
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ABSTRACT: We synthesized biarylalanine-containing hydroxamic acids and tested them on immunoprecipitated HDAC1 and HDAC6 and show a subtype selectivity for HDAC6 that was confirmed in cells by Western blot (tubulin vs histones). We obtained an X-ray structure with a HDAC6-selective inhibitor with the bacterial deacetylase HDAH. Docking studies were carried out using HDAC1 and HDAC6 protein models. Antiproliferative activity was shown on cancer cells for selected compounds.
Bioorganic & medicinal chemistry 03/2008; 16(4):2011-33. · 2.82 Impact Factor
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ABSTRACT: The nuclear import of assembled spliceosomal subunits, the uridine-rich small nuclear ribonucleoprotein particles (U snRNPs), is mediated by a nuclear import receptor adaptor couple of importin beta (Imp beta) and snurportin1 (SPN1). In contrast to any other characterized active nuclear import, the Imp beta/SPN1/U snRNP complex does not require RanGTP for the terminal release from the nuclear basket of the nuclear pore complex (NPC). The crystal structure of Imp beta (127-876) in complex with the Imp beta-binding (IBB) domain of SPN1 (1-65) at 2.8-A resolution reveals that Imp beta adopts an open conformation, which is unique for a functional Imp beta/cargo complex, and rather surprisingly, it resembles the conformation of the Imp beta/RanGTP complex. As binding of RanGTP to Imp beta usually triggers the release of import complexes from the NPC, we propose that by already mimicking a conformation similar to Imp beta/RanGTP the independent dissociation of Imp beta/SPN1 from the nuclear basket is energetically aided.
Journal of Molecular Biology 01/2008; 374(4):1129-38. · 4.00 Impact Factor
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ABSTRACT: The nuclear import of H1 linker histones is mediated by a heterodimer of transport receptors, known as importinbeta and importin7. Interestingly, both importins separately interact with H1, but only as a dimer they facilitate the translocation through the nuclear pore. We identified the H1 binding site of importin7, comprising two extended acidic loops near the C terminus of importin7. The analysis of the H1 import complex assembly by means of isothermal titration calorimetry revealed that the formation of a receptor heterodimer in vitro is an enthalpy-driven process, whereas subsequent binding of H1 to the heterodimer is entropy-driven. Furthermore, we show that the importinbeta binding domain of importin7 plays a key role in the activation of importin7 by importinbeta. This process is allosterically regulated by importinbeta and accounts for a specific tuning of the activity of the importinbeta.importin7 heterodimer. The results presented here provide new insights into cellular strategies to even energy balances in nuclear import and point toward a general regulation of importinbeta-related nuclear import processes.
Journal of Biological Chemistry 05/2007; 282(14):10707-19. · 4.77 Impact Factor
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ABSTRACT: The nuclear import of H1 linker histones is mediated by a heterodimer of transport receptors, known as importinβ and importin7.
Interestingly, both importins separately interact with H1, but only as a dimer they facilitate the translocation through the
nuclear pore. We identified the H1 binding site of importin7, comprising two extended acidic loops near the C terminus of
importin7. The analysis of the H1 import complex assembly by means of isothermal titration calorimetry revealed that the formation
of a receptor heterodimer in vitro is an enthalpy-driven process, whereas subsequent binding of H1 to the heterodimer is entropy-driven. Furthermore, we show
that the importinβ binding domain of importin7 plays a key role in the activation of importin7 by importinβ. This process
is allosterically regulated by importinβ and accounts for a specific tuning of the activity of the importinβ·importin7 heterodimer.
The results presented here provide new insights into cellular strategies to even energy balances in nuclear import and point
toward a general regulation of importinβ-related nuclear import processes.
Journal of Biological Chemistry 04/2007; 282(14):10707-10719. · 4.77 Impact Factor
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ABSTRACT: alpha-Amylases are essential enzymes in alpha-glucan metabolism and catalyse the hydrolysis of long sugar polymers such as amylose and starch. The crystal structure of a previously unidentified amylase (AmyC) from the hyperthermophilic organism Thermotoga maritima was determined at 2.2 Angstroms resolution by means of MAD. AmyC lacks sequence similarity to canonical alpha-amylases, which belong to glycosyl hydrolase families 13, 70 and 77, but exhibits significant similarity to a group of as yet uncharacterized proteins in COG1543 and is related to glycerol hydrolase family 57 (GH-57). AmyC reveals features that are characteristic of alpha-amylases, such as a distorted TIM-barrel structure formed by seven beta-strands and alpha-helices (domain A), and two additional but less well conserved domains. The latter are domain B, which contains three helices inserted in the TIM-barrel after beta-sheet 2, and domain C, a five-helix region at the C-terminus. Interestingly, despite moderate sequence homology, structure comparison revealed significant similarities to a member of GH-57 with known three-dimensional structure, Thermococcus litoralis 4-glucanotransferase, and an even higher similarity to a structure of an enzyme of unknown function from Thermus thermophilus.
Acta Crystallographica Section D Biological Crystallography 04/2006; 62(Pt 3):262-70. · 12.62 Impact Factor
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ABSTRACT: Histone deacetylases (HDACs) are among the most promising targets in cancer therapy. However, structural information greatly enhancing the design of HDAC inhibitors as novel chemotherapeutics has not been available on class 2 HDACs so far. Here we present the structure of the bacterial FB188 HDAH (histone deacetylase-like amidohydrolase from Bordetella/Alcaligenes strain FB188) that reveals high sequential and functional homology to human class 2 HDACs. FB188 HDAH is capable to remove the acetyl moiety from acetylated histones. Several HDAC-specific inhibitors, which have been shown to inhibit tumor activity in both pre-clinical models and in clinical trials, also inhibit FB188 HDAH. We have determined the crystal structure of FB188 HDAH at a resolution of 1.6 angstroms in complex with the reaction product acetate, as well as in complex with the inhibitors suberoylanilide hydroxamic acid (SAHA) and cyclopentyle-propionyle hydroxamic acid (CypX) at a resolution of 1.57 angstroms and 1.75 angstroms, respectively. FB188 HDAH exhibits the canonical fold of class 1 HDACs and contains a catalytic zinc ion. The highest structural diversity compared to class 1 enzymes is found in loop regions especially in the area around the entrance of the active site, indicating significant differences among the acetylated proteins binding to class 1 and 2 HDACs, respectively.
Journal of Molecular Biology 12/2005; 354(1):107-20. · 4.00 Impact Factor
