Tzu-Ping Ko

Academia Sinica, T’ai-pei, Taipei, Taiwan

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Publications (98)508.32 Total impact

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    ABSTRACT: The glycoside hydrolase 10 (GH10) xylanase from Streptomyces sp. 9 (XynAS9) can operate in a broad range of pH and temperature, and thus is a potential candidate for commercial applications. Recently, we engineered XynAS9 via mutating several residues in accordance with the consensus sequences of GH10 thermophilic xylanases in an attempt to improve the enzyme thermostability and thermotolerance. The most promising effects were observed in the double mutant V81P/G82E. In order to investigate the molecular mechanism of the improved thermal profile of XynAS9, complex crystal structures of the wild type (WT) and mutant (MT) enzyme were solved at 1.88-2.05Å resolution. The structures reveal a classical GH10 (β/α)8 TIM-barrel fold. In MT XynAS9, E82 forms several interactions to its neighboring residues, which might aid in stabilizing the local structure. Furthermore, the MT structure showed lower B factors for individual residues compared to the WT structure, reflecting the increased MT protein rigidity. Analyses of the XynAS9 structures also delineate the detailed enzyme-substrate interaction network. More importantly, possible explanations for the enhanced thermal profiles of MT XynAS9 are proposed, which may be a useful strategy for enzyme engineering in the future.
    Journal of biotechnology. 09/2014;
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    ABSTRACT: The multi S1/P1 nuclease AtBFN2 (EC 3.1.30.1) encoded by the Arabidopsis thaliana At1g68290 gene is a glycoprotein that digests RNA, ssDNA, and dsDNA. AtBFN2 depends on three zinc ions for cleaving DNA and RNA at 39-OH to yield 59-nucleotides. In addition, AtBFN29s enzymatic activity is strongly glycan dependent. Plant Zn 2+ -dependent endonucleases present a unique fold, and belong to the Phospholipase C (PLC)/P1 nuclease superfamily. In this work, we present the first complete, ligand-free, AtBFN2 crystal structure, along with sulfate, phosphate and ssDNA co-crystal structures. With these, we were able to provide better insight into the glycan structure and possible enzymatic mechanism. In comparison with other nucleases, the AtBFN2/ligand-free and AtBFN2/PO 4 models suggest a similar, previously proposed, catalytic mechanism. Our data also confirm that the phosphate and vanadate can inhibit the enzyme activity by occupying the active site. More importantly, the AtBFN2/A 5 T structure reveals a novel and conserved secondary binding site, which seems to be important for plant Zn 2+ -dependent endonucleases. Based on these findings, we propose a rational ssDNA binding model, in which the ssDNA wraps itself around the protein and the attached surface glycan, in turn, reinforces the binding complex. Citation: Yu T-F, Maestre-Reyna M, Ko C-Y, Ko T-P, Sun Y-J, et al. (2014) Structural Insights of the ssDNA Binding Site in the Multifunctional Endonuclease AtBFN2 from Arabidopsis thaliana. PLoS ONE 9(8): e105821. doi:10.1371/journal.pone.0105821to J.-F. Shaw), (NSC-103-3113-P-008-001, and NSC-101-2319-B-001-003 (to A. H.-J. Wang). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. (AHJW) . These authors contributed equally to this work.
    PLoS ONE 08/2014; · 3.53 Impact Factor
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    ABSTRACT: The T4 phage protein Arn (Anti restriction nuclease) was identified as an inhibitor of the restriction enzyme McrBC. However, until now, its molecular mechanism remained unclear. In the present study, we used structural approaches to investigate biological properties of Arn. A structural analysis of Arn revealed that its shape and negative charge distribution are similar to dsDNA, suggesting that this protein could act as a DNA mimic. In a subsequent proteomic analysis, we found that the bacterial histone-like protein H-NS interacts with Arn, implying a new function. An electrophoretic mobility shift assay showed that Arn prevents H-NS from binding to the E. coli hns and T4 p8.1 promoters. In vitro gene expression and electron microscopy analyses also indicated that Arn counteracts the gene-silencing effect of H-NS on a reporter gene. Because McrBC and H-NS both participate in the host defense system, our findings suggest that T4 Arn might knock down these mechanisms using its DNA mimicking properties.
    The Journal of biological chemistry. 08/2014;
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    ABSTRACT: Structure-guided design of substrate-binding pocket inversed the stereoselectivity of an NADH-dependent medium-chain alcohol dehydrogenase (MDR) from Prelog to anti-Prelog. The pocket-forming amino acids, especially the unconserved residues as hotspots, play critical roles in directing MDRs' stereoselectivity.
    Chemical communications (Cambridge, England). 05/2014;
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    ABSTRACT: Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel anti-infective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS) from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease.
    PLoS Pathogens 05/2014; 10(5):e1004114. · 8.14 Impact Factor
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    ABSTRACT: The catalytic domain of XynCDBFV, a glycoside hydrolase family 11 (GH11) xylanase from ruminal fungus Neocallimastix patriciarum previously engineered to exhibit higher specific activity and broader pH adaptability, holds great potential in commercial applications. Here, the crystal structures of XynCDBFV and its complex with substrate were determined to 1.27-1.43 Å resolution. These structures revealed a typical GH11 β-jelly-roll fold and detailed interaction networks between the enzyme and ligands. Notably, an extended N-terminal region (NTR) consisting of 11 amino acids was identified in the XynCDBFV structure, which is found unique among GH11 xylanases. The NTR is attached to the catalytic core by hydrogen bonds and stacking forces, along with a disulfide bond between C4 and C172. Interestingly, the NTR deletion mutant retained 61.5% and 19.5% enzymatic activity at 55 oC and 75 oC respectively, compared with the wild-type enzyme, whereas the C4A/C172A mutant showed 86.8% and 23.3% activity. These results suggest that NTR plays a role in XynCDBFV thermostability and the C4/C172 disulfide bond is critical to the NTR-mediated interactions. Furthermore, we also demonstrated that Pichia pastoris produces XynCDBFV with higher catalytic activity at higher temperature than Escherichia coli, in which incorrect NTR folding and inefficient disulfide bond formation might have occurred. In conclusion, these structural and functional analyses of the industrially favored XynCDBFV provide a molecular basis of NTR contribution to its thermostability.
    Journal of Biological Chemistry 03/2014; · 4.65 Impact Factor
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    ABSTRACT: We have obtained the structure of the bacterial diterpene synthase, tuberculosinol/iso-tuberculosinol synthase (Rv3378c) from M. tuberculosis, a target for anti-infective therapies that block virulence factor formation. This phosphatase adopts the same fold as found in the Z or cis-prenyltransferases. We also obtained structures containing the tuberculosinyl diphosphate substrate together with one bisphosphonate inhibitor-bound structure. These structures together with the results of site-directed mutagenesis suggest an unusual mechanism of action involving two Tyr residues. Given the great similarity in local and global structure between Rv3378c and the M. tuberculosis cis-decaprenyl diphosphate synthase, the possibility exists that it may be possible to develop inhibitors that target not only virulence, but also cell wall biosynthesis, based in part on the structures reported here. ſſſ
    Journal of the American Chemical Society 01/2014; · 10.68 Impact Factor
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    ABSTRACT: β-Mannanase has found various biotechnological applications because it is capable of degrading mannans into smaller sugar components. A highly potent example is the thermophilic β-mannanase from Aspergillus niger BK01 (ManBK), which can be efficiently expressed in industrial yeast strains and is thus an attractive candidate for commercial utilizations. In order to understand the molecular mechanism, which helps in strategies to improve the enzyme's performance that would meet industrial demands, 3D-structural information is a great asset. Here, we present the 1.57Å crystal structure of ManBK. The protein adopts a typical (β/α)8 fold that resembles the other GH5 family members. Polysaccharides were subsequently modeled into the substrate binding groove to identify the residues and structural features that may be involved in the catalytic reaction. Based on the structure, rational design was conducted to engineer ManBK in an attempt to enhance its enzymatic activity. Among the 23 mutants that we constructed, the most promising Y216W showed an 18±2.7% increase in specific activity by comparison with the wild type enzyme. The optimal temperature and heat tolerance profiles of Y216W were similar to those of the wild type, manifesting a preserved thermostability. Kinetic studies showed that Y216W has higher kcat values than the wild type enzyme, suggesting a faster turnover rate of catalysis. In this study we applied rational design to ManBK by using its crystal structure as a basis and identified the Y216W mutant that shows great potentials in industrial applications.
    Biochimica et Biophysica Acta 01/2014; · 4.66 Impact Factor
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    ABSTRACT: Escherichia coli phytase (EcAppA) which hydrolyzes phytate has been widely applied in the feed industry, but the need to improve the enzyme activity and thermostability remains. Here, we conduct rational design with two strategies to enhance the EcAppA performance. First, residues near the substrate binding pocket of EcAppA were modified according to the consensus sequence of two highly active Citrobacter phytases. One out of the eleven mutants, V89 T, exhibited 17.5% increase in catalytic activity, which might be a result of stabilized protein folding. Second, the EcAppA glycosylation pattern was modified in accordance with the Citrobacter phytases. An N-glycosylation motif near the substrate binding site was disrupted to remove spatial hindrance for phytate entry and product departure. The de-glycosylated mutants showed 9.6% increase in specific activity. On the other hand, the EcAppA mutants that adopt N-glycosylation motifs from CbAppA showed improved thermostability that three mutants carrying single N-glycosylation motif exhibited 7.2 to 12.8% residual activity after treatment at 80 °C (2.7% for wild type). Furthermore, the mutant carrying all three glycosylation motifs exhibited 27% residual activity. In conclusion, a successful rational design was performed to obtain several useful EcAppA mutants with better properties for further applications.
    Journal of Biotechnology 01/2014; · 3.18 Impact Factor
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    ABSTRACT: Oxidized polyvinyl alcohol hydrolase (OPH) catalyzes the cleavage of C-C bond in β-diketone. It belongs to the α/β-hydrolase family and contains a unique lid region that covers the active site. The lid is the most variable region when pOPH from Pseudomonas sp. VM15C and sOPH from Sphingopyxis sp. 113P3 are compared. The wild-type enzymes and the pOPH mutants W255A, W255Y and W255F were analyzed for lipase activity by using p-nitrophenyl (pNP) esters as the substrates. The wild-type enzymes showed increased Km and decreased kcat/Km with the acyl chain length, and the mutants showed reduced kcat/Km for pNP acetate, indicating the importance of Trp255 in sequestering the active site from solvent. The significantly lower activity for pNP butyrate can be a result of product inhibition, as suggested by the complex crystal structures, in which butyrate, DMSO or PEG occupied the same substrate-binding cleft. The mutant activity was retained with pNP caprylate and pNP laurate as the substrates, reflecting the amphipathic nature of the cleft. Moreover, the disulfide bond formation of Cys257/267 is important for the activity of pOPH, but it is not essential for sOPH, which has a shorter lid structure.
    Biochemical and Biophysical Research Communications 01/2014; · 2.41 Impact Factor
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    ABSTRACT: Pullulanase is a debranching enzyme that specifically hydrolyzes the α-1,6 glycosidic linkage of α-glucans, and has wide industrial applications. Here, we report structural and functional studies of a new thermostable pullulanase from Anoxybacillus sp. LM18-11 (PulA). Based on the hydrolysis products, PulA was classified as a type I pullulanase. It showed maximum activity at 60(o) C and pH 6.0. Kinetic study showed that the specific activity and Km for pullulan of PulA are 750 U/mg and 16.4 μmol/L, respectively. PulA has a half-life of 48 hours at 60(o) C. The remarkable thermostability makes PulA valuable for industrial usage. To further investigate the mechanism of the enzyme, we solved the crystal structures of PulA and its complexes with maltotriose and maltotetraose at 1.75 Å - 2.22 Å resolution. The PulA structure comprises four domains (N1, N2, A, and C). A is the catalytic domain, in which three conserved catalytic residues were identified (D413, E442, and D526). Two molecules of oligosaccharides were seen in the catalytic A domain in a parallel binding mode. Interestingly, another two oligosaccharides molecules were found between the N1 domain and the loop between the third β-strand and the third α-helix in the A domain. Based on sequence alignment and the ligand binding pattern, the N1 domain is identified as a new type of carbohydrate-binding motif and classified to the CBMXX family. The structure solved here is the first structure of pullulanase which has carbohydrate bound to the N1 domain. © Proteins 2013;. © 2013 Wiley Periodicals, Inc.
    Proteins Structure Function and Bioinformatics 12/2013; · 3.34 Impact Factor
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    ABSTRACT: The thermostable 1,3-1,4-β-glucanase PtLic16A from the fungus Paecilomyces thermophila catalyzes stringent hydrolysis of barley β-glucan and lichenan with an outstanding efficiency and has great potential for broad industrial applications. Here, we report the crystal structures of PtLic16A and an inactive mutant E113A in ligand-free form and in complex with the ligands cellobiose, cellotetraose and glucotriose at 1.80Å to 2.25Å resolution. PtLic16A adopts a typical β-jellyroll fold with a curved surface and the concave face forms an extended ligand binding cleft. These structures suggest that PtLic16A might carry out the hydrolysis via retaining mechanism with E113 and E118 serving as the nucleophile and general acid/base, respectively. Interestingly, in the structure of E113A/1,3-1,4-β-glucotriose complex, the sugar bound to the -1 subsite adopts an intermediate-like (α-anomeric) configuration. By combining all crystal structures solved here, a comprehensive binding mode for substrate is proposed. These findings not only help understand the 1,3-1,4-β-glucanase catalytic mechanism but also provide a basis for further enzymatic engineering.
    Biochimica et Biophysica Acta 11/2013; · 4.66 Impact Factor
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    ABSTRACT: DNA mimic proteins are unique factors that control the DNA binding activity of target proteins by directly occupying their DNA binding sites. The extremely divergent amino acid sequences of the DNA mimics make these proteins hard to predict, and although they are likely to be ubiquitous, to date, only a few have been reported and functionally analyzed. Here we used a bioinformatic approach to look for potential DNA mimic proteins among previously reported protein structures. From ∼14 candidates, we selected the Staphylococcus conserved hypothetical protein SSP0047, and used proteomic and structural approaches to show that it is a novel DNA mimic protein. In Staphylococcus aureus, we found that this protein acts as a uracil-DNA glycosylase inhibitor, and therefore named it S. aureus uracil-DNA glycosylase inhibitor (SAUGI). We also determined and analyzed the complex structure of SAUGI and S. aureus uracil-DNA glycosylase (SAUDG). Subsequent BIAcore studies further showed that SAUGI has a high binding affinity to both S. aureus and human UDG. The two uracil-DNA glycosylase inhibitors (UGI and p56) previously known to science were both found in Bacillus phages, and this is the first report of a bacterial DNA mimic that may regulate SAUDG's functional roles in DNA repair and host defense.
    Nucleic Acids Research 10/2013; · 8.81 Impact Factor
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    ABSTRACT: Vaccinia virus envelope protein A27 has multiple functions and is conserved in the Orthopoxvirus genus of the poxvirus family. A27 protein binds to cell surface heparan sulfate, provides an anchor for A26 protein packaging into mature virions, and is essential for egress of mature virus (MV) from infected cells. Here, we crystallized and determined the structure of a truncated form of A27 containing amino acids 21-84, C71/72A (tA27) at 2.2 Å resolution. tA27 protein uses the N-terminal region interface (NTR) to form an unexpected trimeric assembly as the basic unit, which contains two parallel α-helices and one unusual antiparallel α-helix; in a serpentine way, two trimers stack with each other to form a hexamer using the C-terminal region interface (CTR). Recombinant tA27 protein forms oligomers in a concentration-dependent manner in vitro in gel filtration. Analytical ultracentrifugation and multi-angle light scattering revealed that tA27 dimerized in solution and that Leu47, Leu51, and Leu54 at the NTR and Ile68, Asn75, and Leu82 at the CTR are responsible for tA27 self-assembly in vitro. Finally, we constructed recombinant vaccinia viruses expressing full length mutant A27 protein defective in either NTR, CTR, or both interactions; the results demonstrated that wild type A27 dimer/trimer formation was impaired in NTR and CTR mutant viruses, resulting in small plaques that are defective in MV egress. Furthermore, the ability of A27 protein to form disulfide-linked protein complexes with A26 protein was partially or completely interrupted by NTR and CTR mutations, resulting in mature virion progeny with increased plasma membrane fusion activity upon cell entry. Together, these results demonstrate that A27 protein trimer structure is critical for MV egress and membrane fusion modulation. Because A27 is a neutralizing target, structural information will aid the development of inhibitors to block A27 self-assembly or complex formation against vaccinia virus infection.
    PLoS Pathogens 08/2013; 9(8):e1003563. · 8.14 Impact Factor
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    ABSTRACT: β-glucanases have been utilized widely in industry to treat various carbohydrate-containing materials. Recently, the Podospora anserina β-glucanase 131A (PaGluc131A) was identified and classified to a new glycoside hydrolases GH131 family. It shows exo-β-1,3/exo-β-1,6 and endo-β-1,4 glucanase activities with a broad substrate specificity for laminarin, curdlan, pachyman, lichenan, pustulan, and cellulosic derivatives. Here we report the crystal structures of the PaGluc131A catalytic domain with or without ligand (cellotriose) at 1.8 Å resolution. The cellotriose was clearly observed to occupy the +1 to +3 subsites in substrate binding cleft. The broadened substrate binding groove may explain the diverse substrate specificity. Based on our crystal structures, the GH131 family enzyme is likely to carry out the hydrolysis through an inverting catalytic mechanism, in which E99 and E139 are supposed to serve as the general base and general acid.
    Biochemical and Biophysical Research Communications 07/2013; · 2.41 Impact Factor
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    ABSTRACT: DNA mimic proteins are unique factors that control the DNA-binding activity of target proteins by directly occupying their DNA-binding sites. To date, only a few DNA mimic proteins have been reported and their functions analyzed. Here, we present evidence that the Neisseria conserved hypothetical protein DMP12 should be added to this list. Our gel filtration and analytical ultracentrifugation results showed that the DMP12 monomer interacts with the dimeric form of the bacterial histone-like protein HU. Subsequent structural analysis of DMP12 showed that the shape and electrostatic surface of the DMP12 monomer are similar to those of the straight portion of the bent HU-bound DNA and complementary to those of HU protein dimer. DMP12 also protects HU protein from limited digestion by trypsin and enhances the growth rate Escherichia coli. Functionally, HU proteins participate in bacterial nucleoid formation, as well as recombination, gene regulation and DNA replication. The interaction between DMP12 and HU protein might, therefore, play important roles in these DNA-related mechanisms.
    Nucleic Acids Research 03/2013; · 8.81 Impact Factor
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    ABSTRACT: Xylanases are capable of decomposing xylans, the major components in plant cell wall, and releasing the constituent sugars for further applications. Because xylanase is widely used in various manufacturing processes, high specific activity and thermostability are desirable. Here, the wild-type and mutant (E146A and E251A) catalytic domain of xylanase from Thermoanaerobacterium saccharolyticum JW/SL-YS485 (TsXylA) were expressed in Escherichia coli and purified subsequently. The recombinant protein showed optimal temperature and pH of 75(o) C and 6.5, respectively, and it remained fully active even after heat treatment at 75(o) C for one hour. Furthermore, the crystal structures of apo-form wild-type TsXylA and the xylobiose-, xylotriose-, and xylotetraose-bound E146A and E251A mutants were solved by X-ray diffraction to high resolution (1.32-1.66 Å). The protein forms a classic (β/α)8 folding typical of GH10 xylanases. The ligands in substrate-binding groove as well as the interactions between sugars and active-site residues were clearly elucidated by analyzing the complex structures. According to the structural analyses, TsXylA utilizes a double displacement catalytic machinery to carry out the enzymatic reactions. In conclusion, TsXylA is effective under industrially favored conditions, and our findings provide fundamental knowledge which may contribute to further enhancement of the enzyme performance through molecular engineering. Proteins 2013. © 2013 Wiley Periodicals, Inc.
    Proteins Structure Function and Bioinformatics 03/2013; · 3.34 Impact Factor
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    ABSTRACT: Well structured: As a new triose phosphate isomerase (TIM) barrel-fold prenyl transferase, PcrB catalyzes the production of heptaprenylglyceryl phosphate from heptaprenyl diphosphate and glycerol-1-phosphate. Crystal structures of PcrB from Bacillus subtilis and Staphylococcus aureus in complex with ligands were solved, and together with site-directed mutagenesis and bioinformatics analyses, clearly reveal the catalytic mechanism of the enzyme.
    ChemBioChem 01/2013; · 3.74 Impact Factor
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    ABSTRACT: The bi-functional nuclease AtBFN2 from Arabidopsis thaliana (EC 3.1.30.1) depends on zinc ion for cleaving single stranded DNA and RNA to yield 5′-nucleotides. It is a glycoprotein that participates in plant development and differentiation. The crystal structure of AtBFN2 shows a bound sulfate ion in the active site, at the center of the tri-nuclear cluster of zinc ions. The protein folds into a mostly α-helical structure with five short β-strands and contains four disulfide bonds. The zinc ions are coordinated to the side chains of three Asp and five His residues, two backbone atoms of Trp1, the sulfate ion, and a water molecule. An adenine base is bound adjacent to the active site and stacks with Tyr59. The core sugar residues attached to the three N-glycosylation sites of Asn91, Asn110 and Asn184 are also observed. By comparison with the nuclease P1 structure (PDB ID: 1AK0), the AtBFN2-sulfate-adenine complex model suggests a similar catalytic mechanism, in which the reaction starts with in-line attack at the phosphate by a zinc-activated water molecule.
    Biocatalysis and Agricultural Biotechnology. 01/2013; 2(3):191–195.
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    ABSTRACT: Xylan-1,4-β-xylosidase (β-xylosidase) hydrolyzes xylooligomers at the non-reducing end into individual xylose units. Recently, XylC, a β-xylosidase from Thermoanaerobacterium saccharolyticum JW/SL-YS485, was found structurally different from corresponding glycosyl hydrolases in the CAZy database (http://www.cazy.org/), and was subsequently classified as the first member of a novel family of glycosyl hydrolases (GH120). Here, we report three crystal structures of this XylC in complex with Tris, xylobiose and xylose at 1.48-2.05 Å resolution. XylC assembles into a tetramer, and each monomer comprises two distinct domains. The core domain is a right-handed parallel β-helix (residues 1-75, 201-638) and the flanking region (residues 76-200) folds into a β-sandwich domain. The enzyme contains an open carbohydrate-binding cleft, allowing accommodation of longer xylo-oligosaccharides. Based on the crystal structures, we propose that XylC cleaves the glycosidic bond by the retaining mechanism using two acidic residues D382 (nucleophile) and E405 (general acid/base). In addition to the active site, nine other xylose-binding sites were consistently observed in each of the four monomers, providing a possible reason for the high tolerance of product inhibition.
    Biochemical Journal 09/2012; · 4.65 Impact Factor

Publication Stats

1k Citations
508.32 Total Impact Points

Institutions

  • 2002–2014
    • Academia Sinica
      • Institute of Biological Chemistry
      T’ai-pei, Taipei, Taiwan
    • Sapienza University of Rome
      • Department of Biochemical Sciences "Alessandro Rossi Fanelli
      Roma, Latium, Italy
  • 2013
    • Northeast Institute of Geography and Agroecology
      • Tianjin Institute of Industrial Biotechnology
      Peping, Beijing, China
    • Taipei Medical University
      T’ai-pei, Taipei, Taiwan
  • 2012–2013
    • Chinese Academy of Sciences
      Peping, Beijing, China
  • 2006–2011
    • National Yang Ming University
      • • Department and Institute of Pharmacology
      • • Institute of Biochemistry and Molecular Biology
      Taipei, Taipei, Taiwan
  • 2005–2010
    • National Taiwan University
      • Institute of Zoology
      T’ai-pei, Taipei, Taiwan
  • 2003–2007
    • Virginia Commonwealth University
      • Department of Medicinal Chemistry
      Richmond, VA, United States