scholarly journals Comparison of binding interactions of dibromoflavonoids with transthyretin.

2001 ◽  
Vol 48 (4) ◽  
pp. 885-892 ◽  
Author(s):  
T Muzioł ◽  
V Cody ◽  
A Wojtczak
Keyword(s):  
Crystal Structure ◽  
Binding Site ◽  
Competitive Binding ◽  
Hydroxyl Group ◽  
Side Chain ◽  
Strong Interactions ◽  
Binding Interactions ◽  
Methyl Group ◽  
Channel Entrance ◽  
Molecular Architectures

The crystal structure of rat transthyretin (rTTR) complex with the dibromoflavone EMD21388 was determined to 2.3 A resolution and refined to R = 0.203 and Rfree = 0.288. Two different orientations of EMD21388, which differ in the channel penetration by 1.6 A, were found in the A/C binding site of rTTR. The single ligand position observed in the BID site is intermediate between the two positions found in the A/C site. The position of the dibromoflavone in the B/D site is similar to that reported for dibromoaurone in human TTR. The bromine atoms of EMD21388 form strong interactions in the P3 and P3' pockets of rTTR. Due to the different molecular architectures of both ligands, dibromoflavone forms only one interaction with Lys-15 near the channel entrance, while direct interactions with the pair of Lys-15 were reported for dibromoaurone. The C3* methyl group of EMD21388 mediates the bridging interactions between two TTR subunits in the P2 pockets. The interactions of the O2* hydroxyl group of dibromoaurone with the Thr-119 side chain in the P3 pockets are not matched by similar interactions in EMD21388. Both these alternative interactions can explain the competitive binding of 3',5'-dibromoflavonoids to transthyretin.

scholarly journals Characterization of the Acetate Binding Pocket in the Methanosarcina thermophila Acetate Kinase

2005 ◽  
Vol 187 (7) ◽  
pp. 2386-2394 ◽  
Author(s):  
Cheryl Ingram-Smith ◽  
Andrea Gorrell ◽  
Sarah H. Lawrence ◽  
Prabha Iyer ◽  
Kerry Smith ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Binding Site ◽  
Binding Pocket ◽  
Acetate Kinase ◽  
Phosphoryl Group ◽  
Acetyl Phosphate ◽  
Hydrophobic Pocket ◽  
Methanosarcina Thermophila ◽  
Methyl Group ◽  
Substrate Binding Sites

ABSTRACT Acetate kinase catalyzes the reversible magnesium-dependent synthesis of acetyl phosphate by transfer of the ATP γ-phosphoryl group to acetate. Inspection of the crystal structure of the Methanosarcina thermophila enzyme containing only ADP revealed a solvent-accessible hydrophobic pocket formed by residues Val93, Leu122, Phe179, and Pro232 in the active site cleft, which identified a potential acetate binding site. The hypothesis that this was a binding site was further supported by alignment of all acetate kinase sequences available from databases, which showed strict conservation of all four residues, and the recent crystal structure of the M. thermophila enzyme with acetate bound in this pocket. Replacement of each residue in the pocket produced variants with Km values for acetate that were 7- to 26-fold greater than that of the wild type, and perturbations of this binding pocket also altered the specificity for longer-chain carboxylic acids and acetyl phosphate. The kinetic analyses of variants combined with structural modeling indicated that the pocket has roles in binding the methyl group of acetate, influencing substrate specificity, and orienting the carboxyl group. The kinetic analyses also indicated that binding of acetyl phosphate is more dependent on interactions of the phosphate group with an unidentified residue than on interactions between the methyl group and the hydrophobic pocket. The analyses also indicated that Phe179 is essential for catalysis, possibly for domain closure. Alignments of acetate kinase, propionate kinase, and butyrate kinase sequences obtained from databases suggested that these enzymes have similar catalytic mechanisms and carboxylic acid substrate binding sites.

Mapping the active site of papain with the aid of peptide substrates and inhibitors

1970 ◽  
Vol 257 (813) ◽  
pp. 249-264 ◽  
Keyword(s):  
Amino Acid ◽  
Binding Site ◽  
Amino Acid Residue ◽  
Active Site ◽  
Proteolytic Enzymes ◽  
Reaction Rates ◽  
Side Chain ◽  
Peptide Substrates ◽  
Methyl Group ◽  
Kinetics Of

The active site of an enzyme performs the twofold function of binding a substrate and catalysing a reaction. The efficiency of these actions determines the overall activity of the enzyme towards the particular substrate, i.e. determines the specificity of the enzyme. It is therefore possible to obtain information on the active site by the kinetics of the enzyme’s reactions with different substrates and inhibitors. An important feature of the active site is its size. It should be possible to 'measure’ this by using substrates or inhibitors large enough to show up the interactions of the furthermost parts of the binding site. In the present series of investigations on proteolytic enzymes, our approach is to compare the activity of the enzyme towards ( a ) peptides of increasing length, ( b ) diastereoisomeric pairs of peptides in which a particular amino acid residue has been replaced by its antipode, and ( c ) pairs of substrates in which a particular side chain (say a methyl group) has been replaced by another (say an aromatic group). The influence of these changes on reaction rates as a function of distance from the point of cleavage indicates the extent of the active site (Schechter, Abramowitz & Berger 1965; Abramowitz, Schechter & Berger 1967).

scholarly journals Crystal structure and Hirshfeld surface analysis of the methanol solvate of sclareol, a labdane-type diterpenoid

2020 ◽  
Vol 76 (3) ◽  
pp. 294-297
Author(s):  
Memoona Bibi ◽  
M. Iqbal Choudhary ◽  
Sammer Yousuf
Keyword(s):  
Crystal Structure ◽  
Hydrogen Bonds ◽  
Surface Analysis ◽  
Title Compound ◽  
Hirshfeld Surface ◽  
Hirshfeld Surface Analysis ◽  
Hydroxyl Group ◽  
Side Chain ◽  
Compound C ◽  
Salvia Sclarea

The title compound, C20H36O2·CH3OH [systematic name: (3S)-4-[(S)-3-hydroxy-3-methylpent-4-en-1-yl]-3,4a,8,8-tetramethyldecahydronaphthalen-3-ol methanol monosolvate], is a methanol solvate of sclareol, a diterpene oil isolated from the medicinally important medicinal herb Salvia sclarea, commonly known as clary sage. It crystallizes in space group P1 (No. 1) with Z′ = 2. The sclareol molecule comprises two trans-fused cyclohexane rings, each having an equatorially oriented hydroxyl group, and a 3-methylpent-1-en-3-ol side chain. In the crystal, Os—H...Os, Os—H...Om, Om—H...Os and Om—H...Om (s = sclareol, m = methanol) hydrogen bonds connect neighboring molecules into infinite [010] chains. The title compound exhibits weak anti-leishmanial activity (IC50 = 66.4 ± 1.0 µM ml−1) against standard miltefosine (IC50 = 25.8 ± 0.2 µM ml−1).

scholarly journals Crystal Structure of Tetrameric Homoisocitrate Dehydrogenase from an Extreme Thermophile, Thermus thermophilus: Involvement of Hydrophobic Dimer-Dimer Interaction in Extremely High Thermotolerance

2005 ◽  
Vol 187 (19) ◽  
pp. 6779-6788 ◽  
Author(s):  
Junichi Miyazaki ◽  
Kuniko Asada ◽  
Shinya Fushinobu ◽  
Tomohisa Kuzuyama ◽  
Makoto Nishiyama
Keyword(s):  
Crystal Structure ◽  
Binding Site ◽  
Thermal Inactivation ◽  
Hydrophobic Interactions ◽  
Substrate Binding ◽  
Thermus Thermophilus ◽  
Lysine Biosynthesis ◽  
Side Chain ◽  
Substrate Binding Site ◽  
Tetramer Formation

ABSTRACT The crystal structure of homoisocitrate dehydrogenase involved in lysine biosynthesis from Thermus thermophilus (TtHICDH) was determined at 1.85-Å resolution. Arg85, which was shown to be a determinant for substrate specificity in our previous study, is positioned close to the putative substrate binding site and interacts with Glu122. Glu122 is highly conserved in the equivalent position in the primary sequence of ICDH and archaeal 3-isopropylmalate dehydrogenase (IPMDH) but interacts with main- and side-chain atoms in the same domain in those paralogs. In addition, a conserved Tyr residue (Tyr125 in TtHICDH) which extends its side chain toward a substrate and thus has a catalytic function in the related β-decarboxylating dehydrogenases, is flipped out of the substrate-binding site. These results suggest the possibility that the conformation of the region containing Glu122-Tyr125 is changed upon substrate binding in TtHICDH. The crystal structure of TtHICDH also reveals that the arm region is involved in tetramer formation via hydrophobic interactions and might be responsible for the high thermotolerance. Mutation of Val135, located in the dimer-dimer interface and involved in the hydrophobic interaction, to Met alters the enzyme to a dimer (probably due to steric perturbation) and markedly decreases the thermal inactivation temperature. Both the crystal structure and the mutation analysis indicate that tetramer formation is involved in the extremely high thermotolerance of TtHICDH.

scholarly journals Synthetic, structural and biological studies of the ubiquitin system: synthesis and crystal structure of an analogue containing unnatural amino acids

1997 ◽  
Vol 323 (3) ◽  
pp. 727-734 ◽  
Author(s):  
Steven G. LOVE ◽  
Tom W. MUIR ◽  
Robert RAMAGE ◽  
Kevin T. SHAW ◽  
Dmitriy ALEXEEV ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Amino Acids ◽  
Unnatural Amino Acids ◽  
Side Chain ◽  
Hydrophobic Core ◽  
Biological Behaviour ◽  
Methyl Group ◽  
Ubiquitin System ◽  
Biological Studies ◽  
The Stability

Ubiquitin is a 76-amino acid protein involved in the targeting for destruction of proteins in the cell. The protein can readily be synthesized chemically affording an extra dimension to studies of protein stability. Ubiquitin with various modifications to the hydrophobic core has been synthesized. In particular, two core amino acids have been replaced by aminobutyric acid (Val-26) and norvaline (for Ile-30) and the product crystallized. The refined crystal structure shows an overall contraction of the molecule and the side chain of Nva-30 rotates relative to Ile-30. However, the side chain rotation is not sufficient to compensate for the effect of the loss of the methyl group and hence a small cavity is introduced into the structure, which decreases the stability of the protein. The biological behaviour of the modified protein is unaltered. The observed changes in stability are of the magnitude expected for the removal of methyl groups from the hydrophobic core of a protein. Interestingly, the effect appears to be independent of the position of the removed methyl group. The intact structure, but not its stability, is important for recognition by the biological conjugating system.

Crystal structure of hydroxyzine dihydrochloride, C21H29ClN2O2Cl2

2018 ◽  
Vol 34 (1) ◽  
pp. 66-73
Author(s):  
Jordan A. Krueger ◽  
James A. Kaduk ◽  
Amy M. Gindhart ◽  
Thomas N. Blanton
Keyword(s):  
Crystal Structure ◽  
Hydrogen Bond ◽  
Hydrogen Bonds ◽  
Powder Diffraction ◽  
Density Functional ◽  
Hydroxyl Group ◽  
Strong Hydrogen Bond ◽  
Side Chain ◽  
Powder Diffraction File ◽  
X Ray

The crystal structure of hydroxyzine dihydrochloride has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional techniques. Hydroxyzine dihydrochloride crystallizes in space group P21 (#4) with a = 11.48735(10), b = 7.41792(7), c = 14.99234(15) Å, β = 110.4383(10)°, V = 1197.107(13) Å3, and Z = 2. The hydroxyl-containing side chain of the cation is disordered over two conformations, with ~70/30% occupancy. The crystal structure consists of alternating polar (which includes the cation-anion interactions and hydrogen bonds) and nonpolar layers parallel to the ab-plane. The crystal structure is dominated by hydrogen bonds. Each of the protonated nitrogen atoms forms a very strong hydrogen bond to one of the chloride anions. The hydroxyl group forms a strong hydrogen bond to one of the chloride anions in both conformations, and there are subtle differences in the hydrogen bonding patterns between the conformations. The powder pattern is included in the Powder Diffraction File™ as entry 00-066-1603.

Transformations of Steroids by Beauveria bassiana

2005 ◽  
Vol 60 (1-2) ◽  
pp. 103-108 ◽  
Author(s):  
Ewa Huszcza ◽  
Jadwiga Dmochowska-Gładysz ◽  
Agnieszka Bartmańska
Keyword(s):  
Double Bond ◽  
Beauveria Bassiana ◽  
Hydroxyl Group ◽  
Side Chain ◽  
Double Bonds ◽  
Methyl Group ◽  
Group Reduction ◽  
Group A ◽  
Acetyl Group

The course of transformations of testosterone and its derivatives, including compounds with an additional C1,C2 double bond and/or a 17α-methyl group, a 17β-acetyl group or without a 19-methyl group, by a Beauveria bassiana culture was investigated. The fungi promoted hydroxylation of these compounds at position 11α, oxidation of the 17β-hydroxyl group, reduction of the C1,C2 or C4,C5 double bonds and degradation of the progesterone side-chain, leading to testosterone. The structure of 4-ene-3-oxo-steroids had no influence on regio- and stereochemistry of hydroxylation. In a similar manner, dehydroepiandrosterone was hydroxylated by Beauveria bassiana at position 11α, however, a small amount of 7α- hydroxylation product was also formed.

Schistosomal Sulfotransferase Interaction with Oxamniquine Involves Hybrid Mechanism of Induced-fit and Conformational Selection

2020 ◽  
Vol 16 (4) ◽  
pp. 451-459 ◽  
Author(s):  
Fortunatus C. Ezebuo ◽  
Ikemefuna C. Uzochukwu
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Binding Energy ◽  
Binding Site ◽  
Conformational Dynamics ◽  
Side Chain ◽  
Amino Acid Residues ◽  
Conformational Selection ◽  
Hybrid Mechanism ◽  
Dynamics Simulations

Background: Sulfotransferase family comprises key enzymes involved in drug metabolism. Oxamniquine is a pro-drug converted into its active form by schistosomal sulfotransferase. The conformational dynamics of side-chain amino acid residues at the binding site of schistosomal sulfotransferase towards activation of oxamniquine has not received attention. Objective: The study investigated the conformational dynamics of binding site residues in free and oxamniquine bound schistosomal sulfotransferase systems and their contribution to the mechanism of oxamniquine activation by schistosomal sulfotransferase using molecular dynamics simulations and binding energy calculations. Methods: Schistosomal sulfotransferase was obtained from Protein Data Bank and both the free and oxamniquine bound forms were subjected to molecular dynamics simulations using GROMACS-4.5.5 after modeling it’s missing amino acid residues with SWISS-MODEL. Amino acid residues at its binding site for oxamniquine was determined and used for Principal Component Analysis and calculations of side-chain dihedrals. In addition, binding energy of the oxamniquine bound system was calculated using g_MMPBSA. Results: The results showed that binding site amino acid residues in free and oxamniquine bound sulfotransferase sampled different conformational space involving several rotameric states. Importantly, Phe45, Ile145 and Leu241 generated newly induced conformations, whereas Phe41 exhibited shift in equilibrium of its conformational distribution. In addition, the result showed binding energy of -130.091 ± 8.800 KJ/mol and Phe45 contributed -9.8576 KJ/mol. Conclusion: The results showed that schistosomal sulfotransferase binds oxamniquine by relying on hybrid mechanism of induced fit and conformational selection models. The findings offer new insight into sulfotransferase engineering and design of new drugs that target sulfotransferase.

scholarly journals Binding Interactions of Peptide Aptamers

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 6055
Author(s):  
Roger R. C. New ◽  
Tam T. T. Bui ◽  
Michal Bogus
Keyword(s):  
Amino Acid ◽  
Binding Site ◽  
Cyclic Peptides ◽  
Binding Interactions ◽  
Peptide Aptamers ◽  
Linear Peptide ◽  
Signalling Molecules ◽  
Antibody Binding Site ◽  
Linear Chains ◽  
Protein Receptors

Peptide aptamers are short amino acid chains that are capable of binding specifically to ligands in the same way as their much larger counterparts, antibodies. Ligands of therapeutic interest that can be targeted are other peptide chains or loops located on the surface of protein receptors (e.g., GCPR), which take part in cell-to-cell communications either directly or via the intermediary of hormones or signalling molecules. To confer on aptamers the same sort of conformational rigidity that characterises an antibody binding site, aptamers are often constructed in the form of cyclic peptides, on the assumption that this will encourage stronger binding interactions than would occur if the aptamers were simply linear chains. However, no formal studies have been conducted to confirm the hypothesis that linear peptides will engage in stronger binding interactions with cyclic peptides than with other linear peptides. In this study, the interaction of a model cyclic decamer with a series of linear peptide constructs was compared with that of a linear peptide with the same sequence, showing that the cyclic configuration does confer benefits by increasing the strength of binding.

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