scholarly journals Structural basis of sialidase in complex with geranylated flavonoids as potent natural inhibitors

2014 ◽  
Vol 70 (5) ◽  
pp. 1357-1365 ◽  
Author(s):  
Youngjin Lee ◽  
Young Bae Ryu ◽  
Hyung-Seop Youn ◽  
Jung Keun Cho ◽  
Young Min Kim ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Catalytic Domain ◽  
Enzyme Inhibitor ◽  
Gastrointestinal Diseases ◽  
Structural Basis ◽  
Cellular Interactions ◽  
Inhibitory Effects ◽  
Inhibitor Complex ◽  
Structural Framework ◽  
Natural Inhibitors

Sialidase catalyzes the removal of a terminal sialic acid from glycoconjugates and plays a pivotal role in nutrition, cellular interactions and pathogenesis mediating various infectious diseases including cholera, influenza and sepsis. An array of antiviral sialidase agents have been developed and are commercially available, such as zanamivir and oseltamivir for treating influenza. However, the development of bacterial sialidase inhibitors has been much less successful. Here, natural polyphenolic geranylated flavonoids which show significant inhibitory effects againstCp-NanI, a sialidase fromClostridium perfringens, are reported. This bacterium causes various gastrointestinal diseases. The crystal structure of theCp-NanI catalytic domain in complex with the best inhibitor, diplacone, is also presented. This structure explains how diplacone generates a stable enzyme–inhibitor complex. These results provide a structural framework for understanding the interaction between sialidase and natural flavonoids, which are promising scaffolds on which to discover new anti-sialidase agents.

scholarly journals Structural basis of adhesive binding by desmocollins and desmogleins

2016 ◽  
Vol 113 (26) ◽  
pp. 7160-7165 ◽  
Author(s):  
Oliver J. Harrison ◽  
Julia Brasch ◽  
Gorka Lasso ◽  
Phinikoula S. Katsamba ◽  
Goran Ahlsen ◽  
...  
Keyword(s):  
Amino Acids ◽  
Crystal Structures ◽  
Structural Basis ◽  
Cellular Interactions ◽  
Opposite Charge ◽  
Charged Amino Acids ◽  
Structural Framework ◽  
Classical Cadherins ◽  
Coated Bead

Desmosomes are intercellular adhesive junctions that impart strength to vertebrate tissues. Their dense, ordered intercellular attachments are formed by desmogleins (Dsgs) and desmocollins (Dscs), but the nature of trans-cellular interactions between these specialized cadherins is unclear. Here, using solution biophysics and coated-bead aggregation experiments, we demonstrate family-wise heterophilic specificity: All Dsgs form adhesive dimers with all Dscs, with affinities characteristic of each Dsg:Dsc pair. Crystal structures of ectodomains from Dsg2 and Dsg3 and from Dsc1 and Dsc2 show binding through a strand-swap mechanism similar to that of homophilic classical cadherins. However, conserved charged amino acids inhibit Dsg:Dsg and Dsc:Dsc interactions by same-charge repulsion and promote heterophilic Dsg:Dsc interactions through opposite-charge attraction. These findings show that Dsg:Dsc heterodimers represent the fundamental adhesive unit of desmosomes and provide a structural framework for understanding desmosome assembly.

Synthesis and SAR of Thrombin Inhibitors Incorporating a Novel 4-Amino-Morpholinone Scaffold:  Analysis of X-ray Crystal Structure of Enzyme Inhibitor Complex

2003 ◽  
Vol 46 (19) ◽  
pp. 3985-4001 ◽  
Author(s):  
Jonas W. Nilsson ◽  
Ingemar Kvarnström ◽  
Djordje Musil ◽  
Ingemar Nilsson ◽  
Bertil Samulesson
Keyword(s):  
Crystal Structure ◽  
Enzyme Inhibitor ◽  
Thrombin Inhibitors ◽  
X Ray ◽  
Inhibitor Complex

Crystal structure of the catalytic domain of human phenylalanine hydroxylase reveals the structural basis for phenylketonuria

1997 ◽  
Vol 4 (12) ◽  
pp. 995-1000 ◽  
Author(s):  
Heidi Erlandsen ◽  
Fabrizia Fusetti ◽  
Aurora Martinez ◽  
Edward Hough ◽  
Torgeir Flatmark ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Catalytic Domain ◽  
Phenylalanine Hydroxylase ◽  
Structural Basis ◽  
Human Phenylalanine Hydroxylase

scholarly journals X-Ray Crystal Structure of the Multidomain Endoglucanase Cel9G from Clostridium cellulolyticum Complexed with Natural and Synthetic Cello-Oligosaccharides

2003 ◽  
Vol 185 (14) ◽  
pp. 4127-4135 ◽  
Author(s):  
David Mandelman ◽  
Anne Belaich ◽  
J. P. Belaich ◽  
Nushin Aghajari ◽  
Hugues Driguez ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Catalytic Domain ◽  
Cellulose Degradation ◽  
Cellulase Activity ◽  
Structural Basis ◽  
Crystalline Cellulose ◽  
X Ray ◽  
Clostridium Cellulolyticum ◽  
Active Site Cleft ◽  
Cellulose Binding

ABSTRACT Complete cellulose degradation is the first step in the use of biomass as a source of renewable energy. To this end, the engineering of novel cellulase activity, the activity responsible for the hydrolysis of the β-1,4-glycosidic bonds in cellulose, is a topic of great interest. The high-resolution X-ray crystal structure of a multidomain endoglucanase from Clostridium cellulolyticum has been determined at a 1.6-Å resolution. The endoglucanase, Cel9G, is comprised of a family 9 catalytic domain attached to a family IIIc cellulose-binding domain. The two domains together form a flat platform onto which crystalline cellulose is suggested to bind and be fed into the active-site cleft for endolytic hydrolysis. To further dissect the structural basis of cellulose binding and hydrolysis, the structures of Cel9G in the presence of cellobiose, cellotriose, and a DP-10 thio-oligosaccharide inhibitor were resolved at resolutions of 1.7, 1.8, and 1.9 Å, respectively.

scholarly journals Crystal structure of glycosyltrehalose synthase fromSulfolobus shibataeDSM5389

2018 ◽  
Vol 74 (11) ◽  
pp. 741-746
Author(s):  
Nobuo Okazaki ◽  
Michael Blaber ◽  
Ryota Kuroki ◽  
Taro Tamada
Keyword(s):  
Crystal Structure ◽  
Amino Acids ◽  
Catalytic Mechanism ◽  
Catalytic Domain ◽  
Structural Basis ◽  
Hyperthermophilic Archaeon ◽  
X Ray ◽  
X Ray Crystallography ◽  
Sulfolobus Shibatae ◽  
Glucosidic Bond

Glycosyltrehalose synthase (GTSase) converts the glucosidic bond between the last two glucose residues of amylose from an α-1,4 bond to an α-1,1 bond, generating a nonreducing glycosyl trehaloside, in the first step of the biosynthesis of trehalose. To better understand the structural basis of the catalytic mechanism, the crystal structure of GTSase from the hyperthermophilic archaeonSulfolobus shibataeDSM5389 (5389-GTSase) has been determined to 2.4 Å resolution by X-ray crystallography. The structure of 5389-GTSase can be divided into five domains. The central domain contains the (β/α)8-barrel fold that is conserved as the catalytic domain in the α-amylase family. Three invariant catalytic carboxylic amino acids in the α-amylase family are also found in GTSase at positions Asp241, Glu269 and Asp460 in the catalytic domain. The shape of the catalytic cavity and the pocket size at the bottom of the cavity correspond to the intramolecular transglycosylation mechanism proposed from previous enzymatic studies.

scholarly journals Crystal Structure of 12-Lipoxygenase Catalytic-Domain-Inhibitor Complex Identifies a Substrate-Binding Channel for Catalysis

Structure ◽  
2012 ◽  
Vol 20 (9) ◽  
pp. 1490-1497 ◽  
Author(s):  
Shu Xu ◽  
Timothy C. Mueser ◽  
Lawrence J. Marnett ◽  
Max O. Funk
Keyword(s):  
Crystal Structure ◽  
Catalytic Domain ◽  
Substrate Binding ◽  
Inhibitor Complex ◽  
12 Lipoxygenase

scholarly journals The crystal structure of human dipeptidyl peptidase I (cathepsin C) in complex with the inhibitor Gly-Phe-CHN2

2007 ◽  
Vol 401 (3) ◽  
pp. 645-650 ◽  
Author(s):  
Anne Mølgaard ◽  
Jose Arnau ◽  
Conni Lauritzen ◽  
Sine Larsen ◽  
Gitte Petersen ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Enzyme Inhibitor ◽  
Complex Structure ◽  
Dipeptidyl Peptidase ◽  
Cathepsin G ◽  
Native Enzyme ◽  
Zymogen Activation ◽  
Inhibitor Complex ◽  
Enzyme Substrate ◽  
Lysosomal Cysteine Protease

hDDPI (human dipeptidyl peptidase I) is a lysosomal cysteine protease involved in zymogen activation of granule-associated proteases, including granzymes A and B from cytotoxic T-lymphocytes and natural killer cells, cathepsin G and neutrophil elastase, and mast cell tryptase and chymase. In the present paper, we provide the first crystal structure of an hDPPI–inhibitor complex. The inhibitor Gly-Phe-CHN2 (Gly-Phe-diazomethane) was co-crystallized with hDPPI and the structure was determined at 2.0 Å (1 Å=0.1 nm) resolution. The structure of the native enzyme was also determined to 2.05 Å resolution to resolve apparent discrepancies between the complex structure and the previously published structure of the native enzyme. The new structure of the native enzyme is, within the experimental error, identical with the structure of the enzyme–inhibitor complex presented here. The inhibitor interacts with three subunits of hDPPI, and is covalently bound to Cys234 at the active site. The interaction between the totally conserved Asp1 of hDPPI and the ammonium group of the inhibitor forms an essential interaction that mimics enzyme–substrate interactions. The structure of the inhibitor complex provides an explanation of the substrate specificity of hDPPI, and gives a background for the design of new inhibitors.

scholarly journals Inactivation of Recombinant Monocyte cAMP-Specific Phosphodiesterase by cAMP Analog, 8-[(4-Bromo-2,3-Dioxobutyl)thio]Adenosine 3′,5′-Cyclic Monophosphate

Blood ◽  
1997 ◽  
Vol 89 (3) ◽  
pp. 1019-1026 ◽  
Author(s):  
George A. Omburo ◽  
Theodore J. Torphy ◽  
Gilbert Scott ◽  
Susanne Jacobitz ◽  
Roberta F. Colman ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Enzyme Inhibitor ◽  
Order Rate Constant ◽  
Competitive Inhibitor ◽  
Dependent Manner ◽  
Amino Acid Residues ◽  
Concentration Dependent Manner ◽  
Cyclic Monophosphate ◽  
Inhibitor Complex ◽  
Camp Hydrolysis

Abstract Two cAMP analogs, 8- and 2- [(4-bromo-2,3-dioxobutyl) thio]adenosine 3′,5′-cyclic monophosphate (8- and 2-BDB-TcAMP) have been used in probing the catalytic site of recombinant monocyte cAMP-specific phosphodiesterase (PDE4a). 2-BDB-TcAMP is a reversible and competitive inhibitor (Ki = 5.5 μmol/L) of cAMP hydrolysis by PDE4a. 8-BDB-TcAMP irreversibly inactivates the enzyme in a time- and concentration-dependent manner with a second order rate constant of 0.022 mmol/L−1min−1. The rate of inactivation of PDE4a is reduced by the presence of the substrate cAMP and specific inhibitors, rolipram and denbufylline, but not by cGMP or AMP. Reduction of the enzyme-inhibitor complex with sodium [3H]borohydride shows that 1.2 mol of the affinity label/mol of enzyme was incorporated. The radiolabeled peptide is composed of 10 amino acid residues (697 to 706) located near the carboxyl end of the proposed catalytic domain. The peptide (GPGHPPLPDK) has seven nonpolar and aliphatic residues, of which four are proline, giving the peptide a highly structured conformation. This peptide is the first to be identified in the putative catalytic domain involved in substrate recognition.

scholarly journals Structural basis of malaria parasite phenylalanine tRNA-synthetase inhibition by bicyclic azetidines

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Manmohan Sharma ◽  
Nipun Malhotra ◽  
Manickam Yogavel ◽  
Karl Harlos ◽  
Bruno Melillo ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Protein Synthesis ◽  
Single Dose ◽  
Molecular Basis ◽  
Malaria Parasite ◽  
Trna Synthetase ◽  
Structural Basis ◽  
Atp Binding Site ◽  
Structural Framework ◽  
Competitive Inhibitors

AbstractThe inhibition of Plasmodium cytosolic phenylalanine tRNA-synthetase (cFRS) by a novel series of bicyclic azetidines has shown the potential to prevent malaria transmission, provide prophylaxis, and offer single-dose cure in animal models of malaria. To date, however, the molecular basis of Plasmodium cFRS inhibition by bicyclic azetidines has remained unknown. Here, we present structural and biochemical evidence that bicyclic azetidines are competitive inhibitors of L-Phe, one of three substrates required for the cFRS-catalyzed aminoacylation reaction that underpins protein synthesis in the parasite. Critically, our co-crystal structure of a PvcFRS-BRD1389 complex shows that the bicyclic azetidine ligand binds to two distinct sub-sites within the PvcFRS catalytic site. The ligand occupies the L-Phe site along with an auxiliary cavity and traverses past the ATP binding site. Given that BRD1389 recognition residues are conserved amongst apicomplexan FRSs, this work lays a structural framework for the development of drugs against both Plasmodium and related apicomplexans.

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