scholarly journals High-resolution structure of an atypical α-phosphoglucomutase related to eukaryotic phosphomannomutases

2013 ◽  
Vol 69 (10) ◽  
pp. 2008-2016 ◽  
Author(s):  
Przemyslaw Nogly ◽  
Pedro M. Matias ◽  
Matteo de Rosa ◽  
Rute Castro ◽  
Helena Santos ◽  
...  
Keyword(s):  
Crystal Structure ◽  
High Resolution ◽  
Active Site ◽  
Catalytic Mechanism ◽  
Haloacid Dehalogenase ◽  
Enzyme Active Site ◽  
High Resolution Structure ◽  
Dimeric Form ◽  
Strict Specificity ◽  
Resolution Structure

The first structure of a bacterial α-phosphoglucomutase with an overall fold similar to eukaryotic phosphomannomutases is reported. Unlike most α-phosphoglucomutases within the α-D-phosphohexomutase superfamily, it belongs to subclass IIb of the haloacid dehalogenase superfamily (HADSF). It catalyzes the reversible conversion of α-glucose 1-phosphate to glucose 6-phosphate. The crystal structure of α-phosphoglucomutase fromLactococcus lactis(APGM) was determined at 1.5 Å resolution and contains a sulfate and a glycerol bound at the enzyme active site that partially mimic the substrate. A dimeric form of APGM is present in the crystal and in solution, an arrangement that may be functionally relevant. The catalytic mechanism of APGM and its strict specificity towards α-glucose 1-phosphate are discussed.

scholarly journals High Resolution Crystal Structure of the Catalytic Domain of ADAMTS-5 (Aggrecanase-2)

2007 ◽  
Vol 283 (3) ◽  
pp. 1501-1507 ◽  
Author(s):  
Huey-Sheng Shieh ◽  
Karl J. Mathis ◽  
Jennifer M. Williams ◽  
Robert L. Hills ◽  
Joe F. Wiese ◽  
...  
Keyword(s):  
Crystal Structure ◽  
High Resolution ◽  
Catalytic Domain ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Direct Role ◽  
Three Dimensional Structure ◽  
High Resolution Structure ◽  
A Disintegrin And Metalloproteinase ◽  
Resolution Structure

Aggrecanase-2 (a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5)), a member of the ADAMTS protein family, is critically involved in arthritic diseases because of its direct role in cleaving the cartilage component aggrecan. The catalytic domain of aggrecanase-2 has been refolded, purified, and crystallized, and its three-dimensional structure determined to 1.4Å resolution in the presence of an inhibitor. A high resolution structure of an ADAMTS/aggrecanase protein provides an opportunity for the development of therapeutics to treat osteoarthritis.

scholarly journals The Aspergillus fumigatus Sialidase Is a 3-Deoxy-d-glycero-d-galacto-2-nonulosonic Acid Hydrolase (KDNase)

2011 ◽  
Vol 286 (12) ◽  
pp. 10783-10792 ◽  
Author(s):  
Judith C. Telford ◽  
Juliana H. F. Yeung ◽  
Guogang Xu ◽  
Milton J. Kiefel ◽  
Andrew G. Watts ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Aspergillus Fumigatus ◽  
Active Site ◽  
Catalytic Mechanism ◽  
Chair Conformation ◽  
Boat Conformation ◽  
Transition State Analog ◽  
Acetylneuraminic Acid ◽  
Nonulosonic Acid ◽  
Resolution Structure

Aspergillus fumigatus is a filamentous fungus that can cause severe respiratory disease in immunocompromised individuals. A putative sialidase from A. fumigatus was recently cloned and shown to be relatively poor in cleaving N-acetylneuraminic acid (Neu5Ac) in comparison with bacterial sialidases. Here we present the first crystal structure of a fungal sialidase. When the apo structure was compared with bacterial sialidase structures, the active site of the Aspergillus enzyme suggested that Neu5Ac would be a poor substrate because of a smaller pocket that normally accommodates the acetamido group of Neu5Ac in sialidases. A sialic acid with a hydroxyl in place of an acetamido group is 2-keto-3-deoxynononic acid (KDN). We show that KDN is the preferred substrate for the A. fumigatus sialidase and that A. fumigatus can utilize KDN as a sole carbon source. A 1.45-Å resolution crystal structure of the enzyme in complex with KDN reveals KDN in the active site in a boat conformation and nearby a second binding site occupied by KDN in a chair conformation, suggesting that polyKDN may be a natural substrate. The enzyme is not inhibited by the sialidase transition state analog 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (Neu5Ac2en) but is inhibited by the related 2,3-didehydro-2,3-dideoxy-d-glycero-d-galacto-nonulosonic acid that we show bound to the enzyme in a 1.84-Å resolution crystal structure. Using a fluorinated KDN substrate, we present a 1.5-Å resolution structure of a covalently bound catalytic intermediate. The A. fumigatus sialidase is therefore a KDNase with a similar catalytic mechanism to Neu5Ac exosialidases, and this study represents the first structure of a KDNase.

scholarly journals Genuine open form of the pentameric ligand-gated ion channel GLIC

2015 ◽  
Vol 71 (3) ◽  
pp. 454-460 ◽  
Author(s):  
Zaineb Fourati ◽  
Ludovic Sauguet ◽  
Marc Delarue
Keyword(s):  
Crystal Structure ◽  
High Resolution ◽  
Conformational Changes ◽  
Computational Studies ◽  
Potential Influence ◽  
X Ray ◽  
Correct Assignment ◽  
High Resolution Structure ◽  
Fast Chemical ◽  
Resolution Structure

Pentameric ligand-gated ion channels (pLGICs) mediate fast chemical neurotransmission of nerve signalling in the central and peripheral nervous systems. GLIC is a bacterial homologue of eukaryotic pLGIC, the X-ray structure of which has been determined in three different conformations. GLIC is thus widely used as a model to study the activation and the allosteric transition of this family of receptors. The recently solved high-resolution structure of GLIC (2.4 Å resolution) in the active state revealed two bound acetate molecules in the extracellular domain (ECD). Here, it is shown that these two acetates exactly overlap with known sites of pharmacological importance in pLGICs, and their potential influence on the structure of the open state is studied in detail. Firstly, experimental evidence is presented for the correct assignment of these acetate molecules by using the anomalous dispersion signal of bromoacetate. Secondly, the crystal structure of GLIC in the absence of acetate was solved and it is shown that acetate binding induces local conformational changes that occur in strategic sites of the ECD. It is expected that this acetate-free structure will be useful in future computational studies of the gating transition in GLIC and other pLGICs.

scholarly journals High-resolution structure of AKR1a4 in the apo form and its interaction with ligands

2012 ◽  
Vol 68 (11) ◽  
pp. 1271-1274 ◽  
Author(s):  
Frédérick Faucher ◽  
Zongchao Jia
Keyword(s):  
Crystal Structure ◽  
High Resolution ◽  
Aldehyde Reductase ◽  
Founding Member ◽  
High Resolution Structure ◽  
Ascorbate Biosynthesis ◽  
Resolution Structure

Aldo-keto reductase 1a4 (AKR1a4; EC 1.1.1.2) is the mouse orthologue of human aldehyde reductase (AKR1a1), the founding member of the AKR family. As an NADPH-dependent enzyme, AKR1a4 catalyses the conversion of D-glucuronate to L-gulonate. AKR1a4 is involved in ascorbate biosynthesis in mice, but has also recently been found to interact with SMAR1, providing a novel mechanism of ROS regulation by ATM. Here, the crystal structure of AKR1a4 in its apo form at 1.64 Å resolution as well as the characterization of the binding of AKR1a4 to NADPH and P44, a peptide derived from SMAR1, is presented.

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