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An informative and critical review of the contributions of crystallography and NMR to the design of HIV protease inhibitors, including several case studies.
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••] describe the structures of complexes of two enediyne antitumour antibiotics with cognate oligonucleotides. These structures provide explanations for the observed sequence-specificity of the two compounds, and show how the binding positions the pro-radical centres appropriately for double-strand cleavage.
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Describes the use of residual dipolar couplings in proteins partly oriented in a dilute solution of phospholipid bicelles to obtain structural information. This is an important addition to the available methods for obtaining structural information from NMR.
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1H cross-peak in, for example, an HMQC spectrum. This paper describes a method for selecting only the narrowest component, making it possible to obtain sharp lines from large proteins, and thus promising to extend substantially the upper size limit for studying proteins by NMR.
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1H cross-peak in, for example, an HMQC spectrum. This paper describes a method for selecting only the narrowest component, making it possible to obtain sharp lines from large proteins, and thus promising to extend substantially the upper size limit for studying proteins by NMR.
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An informative comparison of the structural ensembles obtained by NMR and by molecular dynamics simulations for two very different systems. The rather surprising conclusion is that the large-scale correlated motions indicated by the two very different methods are quite similar. This lends support to the idea that less well-defined regions of solution structures determined by NMR are likely to be mobile. The comparison also leads to a proposal for an improved selection criterion for inclusion of structures in the 'NMR ensemble' to ensure that amplitudes of motion are better represented.
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•], provides a detailed analysis of the mobility of a discrete region in intestinal fatty-acid binding protein and the way in which this changes on fatty acid binding. It is proposed that this mobility is required for access of the fatty acid to its binding site.
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Changes in the NMR-derived motional parameters of the insulin receptor substrate 1 phosphotyrosine binding domain upon binding to an interleukin 4 receptor phosphopeptide
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15N relaxation studies show that many residues involved in peptide binding are motionally restricted in the free protein; others become more restricted on peptide binding - including some residues that do not contact the ligand directly.
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The NMR structure of this peptide-SH3 domain complex shows that the peptide residues in the first and second subsites are well-ordered, but a range of evidence is presented for mobility in the third subsite. The possibility of fluctuating hydrogen bonding interactions is discussed in which a donor on the peptide or protein can interact with alternative acceptors on the other partner.
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2H relaxation measurements on methyl groups of two SH2 domains were used to probe changes in their dynamics on binding peptides. Both increases and decreases in mobility were observed, and the two domains showed different patterns of behaviour. The paper contains a valuable discussion of the relationships between dynamics, binding thermodynamics and specificity.
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2H relaxation measurements on methyl groups of two SH2 domains were used to probe changes in their dynamics on binding peptides. Both increases and decreases in mobility were observed, and the two domains showed different patterns of behaviour. The paper contains a valuable discussion of the relationships between dynamics, binding thermodynamics and specificity.
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The catalytic mechanism of cytochrome P450 BM3 involves a 6 Å movement of the bound substrate on reduction
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The conformation of coenzyme A bound to chloramphenicol acetyltransferase determined by transferred NOE experiments
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+ bound to lactate dehydrogenase determined by nuclear magnetic resonance with suppression of spin diffusion
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+ was similar to that seen in the crystal, but that about the nicotinamide glycosidic bond was not, and the coexistence of two conformations about this bond in the complex is suggested
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+ was similar to that seen in the crystal, but that about the nicotinamide glycosidic bond was not, and the coexistence of two conformations about this bond in the complex is suggested.
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Cox JR, Serpersu EH Biologically important conformations of aminoglycoside antibiotics bound to an aminoglycoside 3′-phosphotransferase as determined by transferred nuclear Overhauser effect spectroscopy. Biochemistry. 36:1997;2353-2359.
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Solution structure of glutathione bound to human glutathione transferase P1-1: Comparison of NMR measurements with the crystal structure
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Transferred NOE experiments lead to a conformation of bound glutathione that has a similar backbone conformation but sidechain conformations that differ from those seen in the crystal. The origins of this difference are discussed in the light of docking calculations and kinetic experiments; it is concluded that the NMR structure may correspond to that of a 'pre-complex' (see also [58])
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Nicotra M, Paci M, Sette M, Oakley AJ, Parker MW, Lo Bello M, Caccuri AM, Federici G, Ricci G Solution structure of glutathione bound to human glutathione transferase P1-1: comparison of NMR measurements with the crystal structure. Biochemistry. 37:1998;3020-3027. Transferred NOE experiments lead to a conformation of bound glutathione that has a similar backbone conformation but sidechain conformations that differ from those seen in the crystal. The origins of this difference are discussed in the light of docking calculations and kinetic experiments; it is concluded that the NMR structure may correspond to that of a 'pre-complex' (see also [58]).
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66
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Escherichia coli β-galactosidase recognizes a high-energy conformation of C-lactose, a non-hydrolyzable substrate analogue. NMR and modelling studies of the molecular complex
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Transferred NOE experiments indicate that C-lactose (in which the glycosidic oxygen of lactose is replaced by a methylene group) bound to β-galactosidase adopts a conformation which is only slightly populated (~5%) in the free ligand.
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Espinosa JF, Montero E, Vian A, García JL, Dietrich H, Schmidt RR, Martín-Lomas M, Imberty A, Cañada FJ, Jiménez-Barbero J Escherichia coli β-galactosidase recognizes a high-energy conformation of C-lactose, a non-hydrolyzable substrate analogue. NMR and modelling studies of the molecular complex. J Am Chem Soc. 120:1998;1309-1318. Transferred NOE experiments indicate that C-lactose (in which the glycosidic oxygen of lactose is replaced by a methylene group) bound to β-galactosidase adopts a conformation which is only slightly populated (~5%) in the free ligand.
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NMR studies of the conformation of thiocellobiose bound to a β-glucosidase from Streptomyces sp.
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x tetrasaccharide free in solution and bound to E-, P-, and L-selectin
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x tetrasaccharide, the sialyl residue is attached via a flexible glycosidic linkage to a rigid branched trisaccharide. A careful quantitative analysis of transferred NOE experiments shows that different conformers of the tetrasaccharide are recognised by E- and P-selectin on the one hand and L-selectin on the other.
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x tetrasaccharide, the sialyl residue is attached via a flexible glycosidic linkage to a rigid branched trisaccharide. A careful quantitative analysis of transferred NOE experiments shows that different conformers of the tetrasaccharide are recognised by E- and P-selectin on the one hand and L-selectin on the other.
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J Am Chem Soc
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69
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Human cytomegalovirus protease complexes its substrate recognition sequences in an extended peptide conformation
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LaPlante SR, Aubry N, Bonneau PR, Cameron DR, Lagacé L, Massariol M-J, Montpetit H, Plouffe C, Kawai SH, Fulton BDet al. Human cytomegalovirus protease complexes its substrate recognition sequences in an extended peptide conformation. Biochemistry. 37:1998;9793-9801.
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Laplante, S.R.1
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Massariol, M.-J.6
Montpetit, H.7
Plouffe, C.8
Kawai, S.H.9
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70
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0032519515
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Mapping the active site of factor Xa by selective inhibitors: And NMR and MD study
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Two peptide inhibitors of factor Xa, obtained by library screening, were studied by transferred NOE experiments. Structures were calculated both for the peptides in isolation and in the binding site (see also [58]), systematically exploring possible orientations in the site. The model of the complex obtained, suggesting that the inhibitors bind differently from the substrate, made it possible to explain the specificity of the inhibitors.
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Fraternali F, Do Q-T, Doan B-T, Atkinson RA, Palmas P, Sklenar V, Safar P, Wildgoose P, Strop P, Saudek V Mapping the active site of factor Xa by selective inhibitors: and NMR and MD study. Proteins Struct Func Genet. 30:1998;264-274. Two peptide inhibitors of factor Xa, obtained by library screening, were studied by transferred NOE experiments. Structures were calculated both for the peptides in isolation and in the binding site (see also [58]), systematically exploring possible orientations in the site. The model of the complex obtained, suggesting that the inhibitors bind differently from the substrate, made it possible to explain the specificity of the inhibitors.
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Proteins Struct Func Genet
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Fraternali, F.1
Do, Q.-T.2
Doan, B.-T.3
Atkinson, R.A.4
Palmas, P.5
Sklenar, V.6
Safar, P.7
Wildgoose, P.8
Strop, P.9
Saudek, V.10
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71
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0032548447
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Insights into tyrosine phosphorylation control of protein-protein association from the NMR structure of a band 3 peptide inhibitor bound to glyceraldehyde-3-phosphate dehydrogenase
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Eisenmesser EZ, Post CB Insights into tyrosine phosphorylation control of protein-protein association from the NMR structure of a band 3 peptide inhibitor bound to glyceraldehyde-3-phosphate dehydrogenase. Biochemistry. 37:1998;867-877.
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Eisenmesser, E.Z.1
Post, C.B.2
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72
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0032575343
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NMR studies on the conformation of the CD4 36-59 peptide bound to HIV gp120
-
Transferred NOE experiments, including identification of spin diffusion effects, led to a well-defined backbone conformation for residues 42-49 of the peptide corresponding to CD4 residues 36-59 when bound to HIV-1 gp120. The calculated conformation differed from that seen in either of two crystal structures of CD4, suggesting a change in conformation on binding.
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Gizachew D, Moffett DB, Busse SC, Westler WM, Dratz EA, Teintze M NMR studies on the conformation of the CD4 36-59 peptide bound to HIV gp120. Biochemistry. 37:1998;10616-10625. Transferred NOE experiments, including identification of spin diffusion effects, led to a well-defined backbone conformation for residues 42-49 of the peptide corresponding to CD4 residues 36-59 when bound to HIV-1 gp120. The calculated conformation differed from that seen in either of two crystal structures of CD4, suggesting a change in conformation on binding.
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(1998)
Biochemistry
, vol.37
, pp. 10616-10625
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-
Gizachew, D.1
Moffett, D.B.2
Busse, S.C.3
Westler, W.M.4
Dratz, E.A.5
Teintze, M.6
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73
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0031558779
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Structure of the fifth EGF-like domain of thrombomodulin: An EGF-like domain with a novel disulfide-bonding pattern
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•] show the value of transferred NOE experiments in giving access to the peptide conformation in the bound state, as a model for the design of peptidomimetic drugs.
-
•] show the value of transferred NOE experiments in giving access to the peptide conformation in the bound state, as a model for the design of peptidomimetic drugs.
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(1997)
J Mol Biol
, vol.273
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Benitez, B.A.S.1
Hunter, M.J.2
Meininger, D.P.3
Komives, E.A.4
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