Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The 1H nuclear magnetic resonance (n.m.r.) assignments for the aromatic spin systems of the four tyrosines and four phenylalanines in the basic pancreatic trypsin inhibitor (BPTI) were reinvestigated using novel 13C-1H heteronuclear two-dimensional experiments. Resonance lines which are degenerate in homonuclear 1H n.m.r. spectra could thus be resolved. Based on this new evidence the previous assignments for Phe22 and Phe33 had to be corrected. This affects the earlier conclusions on aromatic ring flips in BPTI in that Phe22 is rotating rapidly on the n.m.r. time scale at 36 degrees C, rather than being immobilized up to 80 degrees C.
J Mol Biol 1987 Jul 05
PMID:Reinvestigation of the aromatic side-chains in the basic pancreatic trypsin inhibitor by heteronuclear two-dimensional nuclear magnetic resonance. 244 16

A set of conformational restraints derived from nuclear magnetic resonance (n.m.r.) measurements on solutions of the basic pancreatic trypsin inhibitor (BPTI) was used as input for distance geometry calculations with the programs DISGEO and DISMAN. Five structures obtained with each of these algorithms were systematically compared among themselves and with the crystal structure of BPTI. It is clear that the protein architecture observed in single crystals of BPTI is largely preserved in aqueous solution, with local structural differences mainly confined to the protein surface. The results confirm that protein conformations determined in solution by combined use of n.m.r. and distance geometry are a consequence of the experimental data and do not depend significantly on the algorithm used for the structure determination. The data obtained further provide an illustration that long intramolecular distances in proteins, which are comparable with the radius of gyration, are defined with high precision by relatively imprecise nuclear Overhauser enhancement measurements of a large number of much shorter distances.
J Mol Biol 1987 Aug 05
PMID:Protein structures in solution by nuclear magnetic resonance and distance geometry. The polypeptide fold of the basic pancreatic trypsin inhibitor determined using two different algorithms, DISGEO and DISMAN. 244 92

The attempt is made to find new correlations between local structural characteristics of proteins and the hydrogen exchange rates of their individual main-chain amides, and to relate such correlations to possible mechanisms of hydrogen exchange. It is found that in bovine pancreatic trypsin inhibitor (BPTI) the surface area buried by a particular residue and its neighbors correlates with the exchange rate of the main-chain amide of that residue. As the area buried by a particular fragment can be associated with the stabilization of the protein structure by this fragment, the correlation suggests a role for the energetics of the local unfolding in the mechanism of hydrogen exchange. Calculations based on the assumption that the exchange mechanism involves local unfolding lead to quantitative agreement between the calculated and experimentally measured exchange rates for 80% of the amides of BPTI that are buried or hydrogen bonded to the main-chain or to internal water molecules. The same degree of correlation is found between the calculated exchange rates and partial exchange data for ribonuclease S, hen lysozyme and cytochrome c. A similarly strong correlation is found between calculated exchange rates and the exchange rates of ribonuclease A determined by neutron diffraction in the crystal. The criteria of correlation are, however, less stringent in this case because of the experimental errors, which are larger than for solution data. It is suggested that the observed correlation be used for predictions of hydrogen exchange rates in proteins.
J Mol Biol 1987 Nov 20
PMID:Correlation between calculated local stability and hydrogen exchange rates in proteins. 244 80

The structure of bovine pancreatic trypsin inhibitor has been solved in a new crystal form III. The crystals belong to space group P2(1)2(1)2 with a = 55.2 A, b = 38.2 A, c = 24.05 A. The structure was solved on the basis of co-ordinates of forms I and II of the inhibitor by molecular replacement, and the X-ray data extending to 1.7 A were used in a restrained least-squares refinement. The final R factor was 0.16, and the deviation of bonded distances from ideality was 0.020 A. Root-mean-square discrepancy between C alpha co-ordinates of forms III and I are 0.47 A, whilst between forms II and III the discrepancy is 0.39 A. These deviations are about a factor of 3 larger than the expected experimental errors, showing that true differences exist between the three crystal forms. Two residues (Arg39 and Asp50) were modeled with two positions for their side-chains. The final model includes 73 water molecules and one phosphate group bound to the protein. Sixteen water molecules occupy approximately the same positions in all three crystal forms studied to date, indicating their close association with the protein molecule. Temperature factors also show a high degree of correlation between the three crystal forms.
J Mol Biol 1987 Dec 05
PMID:Structure of form III crystals of bovine pancreatic trypsin inhibitor. 244 84

The kinetics of the disulfide-coupled unfolding-refolding transition of a mutant form of bovine pancreatic trypsin inhibitor (BPTI) lacking Cys-14 and -38 were measured and compared to previous results for the wild-type protein and other modified forms. The altered cysteines, which were changed to serine in the mutant protein, are normally paired in a disulfide in the native protein but from disulfides with Cys-5 in two-disulfide kinetic intermediates during folding. Although the mutant protein could fold efficiently, the kinetics of both folding and unfolding were altered, reflecting the roles of these cysteines in the two-disulfide intermediates with "wrong" disulfides. The intramolecular rate constant for the formation of the second disulfide of the native mutant protein was more than 10(3)-fold lower than that for the formation of a second disulfide during the refolding of the wild-type protein. The observed rate of unfolding of the mutant protein was also lower than that of the wild-type protein, demonstrating that the altered cysteines are involved in the intramolecular rearrangements that are the rate-determining step in the unfolding of the wild-type protein. These results confirm the previous conclusion [Creighton, T.E. (1977) J. Mol. Biol. 113, 275-293] that the energetically preferred pathway for folding and unfolding of BPTI includes intramolecular rearrangements of intermediates in which Cys-14 and -38 are paired in disulfides not present in the native protein. The present results are also consistent with other, less detailed, studies with similar mutants lacking Cys-14 and -38 [Marks, C.B., Naderi, H., Kosen, P.A., Kuntz, I.D., & Anderson, S. (1987) Science (Washington, D.C.) 235, 1370-1371].
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PMID:Kinetic analysis of the folding and unfolding of a mutant form of bovine pancreatic trypsin inhibitor lacking the cysteine-14 and -38 thiols. 245 56

The experimental inelastic neutron scattering spectrum of a protein, the bovine pancreatic trypsin inhibitor (BPTI), in a powder sample is presented together with the generalized density of states, G(omega), as a function of the frequency, omega, derived from the scattering data. The experimental results are compared with calculations from two different normal mode analyses of BPTI. One of these, based on an improved model, gives a calculated spectrum and density of states in general agreement with those obtained experimentally; the other, based on an earlier model, shows considerable disagreement. The important improvements in the newer normal mode analysis are the explicit treatment of all atoms (non-polar as well as polar hydrogens are included) and a modified truncation scheme for the long-range electrostatic interactions. The fact that the inelastic neutron scattering measurements can distinguish between the two theoretical models makes clear their utility for the analysis of protein dynamics.
J Mol Biol 1988 Aug 20
PMID:Inelastic neutron scattering analysis of picosecond internal protein dynamics. Comparison of harmonic theory with experiment. 245 99

An implementation of the variable-target-function procedure, first introduced by Braun and Go [W. Braun and N. Go, J. Mol. Biol. 186, 611-626 (1985)], has been used to generate conformations of the small protein bovine pancreatic trypsin inhibitor (BPTI), given a limited set of simulated data that could be obtained by nuclear magnetic resonance (NMR) techniques. A hybrid strategy was also used to calculate conformations of BPTI, given the same information. In the hybrid strategy, low-energy structures of medium-size fragments (decapeptides) of BPTI were generated using the variable-target-function method, followed by restrained energy optimization. The low-energy conformations were used as a basis to build up the complete fifty-eight-residue BPTI molecule. By using the variable-target-function approach, in which energy considerations were not introduced until full conformations of the entire BPTI molecule had been generated, it was not possible to obtain calculated structures with rms deviations from the X-ray conformation of less than 1.6 A for the alpha-carbons. On the other hand, with the hybrid strategy, which involved the consideration of realistic energy terms in the early stages of the calculations, it was possible to calculate low-energy conformations of BPTI with rms deviations from the X-ray structure of 1.06 to 1.50 A for the alpha-carbons. When the rms deviations were computed along the amino acid sequence, it was found that there was a good correlation between deviations among the calculated structures and deviations from the X-ray structure.
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PMID:Variable-target-function and build-up procedures for the calculation of protein conformation. Application to bovine pancreatic trypsin inhibitor using limited simulated nuclear magnetic resonance data. 248 59

Recent findings of the protease inhibitor domain in amyloid precursor protein of Alzheimer's disease (APPI) raised a novel hypothesis on the mechanism of amyloid deposition in the brain. APPI has significant amino acid sequence homology with Kunitz-type basic trypsin inhibitor super-family proteins, and the gene expression product showed real inhibitory activity. Since the three-dimensional model of APPI would help in understanding biological phenomena in molecular detail, we constructed an atomic model of APPI based on the structure of bovine pancreatic trypsin inhibitor (BPTI). The substitution of BPTI side chains by best-fitting corresponding amino acid structures was followed by the removal of van der Waals overlappings by molecular mechanics energy minimization with the AMBER force field, to give the feasible model of APPI. We also built serine protease models based on the structure of trypsin and investigated the target enzyme specificity of the inhibitory activity by the active-site mapping method. The models can explain the relative enzyme spectra of APPI and BPTI.
J Mol Graph 1989 Dec
PMID:Structure prediction of protease inhibitor region in amyloid precursor protein of Alzheimer's disease. 248 10

Employing the known three-dimensional (3D) structure of trypsin, we constructed simple graphics models of human-activated protein C and thrombin catalytic domains. Considering the structural analysis of bovine trypsin and pancreatic trypsin inhibitor complex, the difference of active-site amino acid sequences of human protein C inhibitor and antithrombin III and their inhibitory selectivity toward activated protein C and thrombin, we estimated the enzymatic subsites of activated protein C and thrombin and mapped them on the graphics models. Predicted favorable contacts can explain substrate selectivity of the enzymes. In this study, we used two types of modified ALPHA representations extensively. Since almost no report on the 3D structure of a blood coagulation factor has appeared and even an extensive molecular mechanics or dynamics calculation cannot produce satisfying results, simple graphics representation has several advantages.
J Mol Graph 1989 Sep
PMID:Mapping active sites of blood coagulation serine proteases--activated protein C and thrombin--on simple graphics models. 248 54

The protein and gene sequences of the cowpea Bowman-Birk type trypsin inhibitor which confers enhanced insect resistance to transgenic tobacco plants, and of cowpea trypsin/chymotrypsin inhibitors are presented. There are regions of high conservation and high divergence within the 5' leader, mature protein and 3' non-coding regions of the Bowman-Birk inhibitors and in the genes which encode them in different members of this family within the Leguminosae. The practical implications of this finding for studies on the evolution of plants and the utilization of these genes for enhancing insect resistance is discussed.
Plant Mol Biol 1989 Dec
PMID:Protein and cDNA sequences of Bowman-Birk protease inhibitors from the cowpea (Vigna unguiculata Walp.). 249 85


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