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PubMed1993

Integration of 3-D medical imaging and rapid prototyping to create stereolithographic models.

This paper describes current research into the creation of solid models which replicate anatomical structures using rapid prototyping techniques. Stereolithography is particularly efficient in the production of highly-complex structures. This technique was applied to the fabrication of a plastic model of a human skull. A geometric definition of the object was obtained by transferring the three-dimensional medical image volume (x-ray CT) and processing the data on a computer graphics workstation. A 3-D biomedical visualisation software package (ANALYZETM) was used to perform segmentation of structures. A 3-D triangular-mesh representation of the selected structure was calculated and converted to a format suitable for processing and construction using stereolithography (SLA). Improvements in the quality of the anatomical model produced will result from improved data processing techniques. Future work is proposed to investigate the influence of imaging parameters and data processing techniques on the resultant plastic models.

Humans↗
PubMed2000

Structure of triamidoaluminum complexes: a theoretical ab initio/IMOMM study.

The electronic structure of three-coordinated complexes of aluminum Al(NR2)3 has been studied through theoretical calculations. In the unsubstituted system Al(NH2)3, ab initio calculations (MP2/6-31G(d,p) level) show that the optimal geometry results from a conrotatory motion of the three amido substituents starting from the fully conjugated planar species. The energy difference between these two structures is found to be small (less than 0.5 kcal/mol). In methylated species Al(NMe2)3, steric effects become important and the planar geometry is destabilized. The conrotatory geometry corresponds to the absolute minimum and is located 14.2 kcal/mol below the planar structure (MP2/6-31G(d,p) level). Several coupled motions of the amido substituents have been computed and have been found to stabilize the system with respect to the fully conjugated structure. A rough estimate of the steric repulsion is calculated by comparison between the unsubstituted and methylated species. Finally, the real molecules Al[N(SiMe3)2]3 and Al(NiPr2)3 have been studied through a coupled quantum mechanics/molecular mechanics method. In accordance with the experimental data, it is found that the conrotatory minimum is the absolute minimum in the R = SiMe3 case whereas a less symmetrical minimum is found in the R = iPr case. In this last minimum, an amido group is almost deconjugated and the two other groups move in a conrotatory manner. The different behavior of these two systems may originate from the quasi-spherical shape of the SiMe3 group, which leads to unavoidable steric repulsion.

Journal Article↗
PubMed2004

Rational redesign of inhibitors of furin/kexin processing proteases by electrostatic mutations.

AIM: To model the three-dimensional structure and investigate the interaction mechanism of the proprotein convertase furin/kexin and their inhibitors (eglin c mutants). METHODS: The three-dimensional complex structures of furin/kexin with its inhibitors, eglin c mutants, were generated by modeller program using the newly published X-ray crystallographical structures of mouse furin and yeast kexin as templates. The electrostatic interaction energy of each complex was calculated and the results were compared with the experimentally determined inhibition constants to find the correlation between them. RESULTS: High quality models of furin/kexin-eglin c mutants were obtained and used for calculation of the electrostatic interaction energies between the proteases and their inhibitors. The calculated electrostatic energies of interaction showed a linear correlation to the experimental inhibition constants. CONCLUSION: The modeled structures give good explanations of the specificity of eglin c mutants to furin/kexin. The electrostatic interactions play important roles in inhibitory activity of eglin c mutants to furin/kexin. The results presented here provided quantitative structural and functional information concerning the role of the charge-charge interactions in the binding of furin/kexin and their inhibitors.

Animals↗
PubMed1990

Conformational changes in cytochrome c and cytochrome oxidase upon complex formation: a resonance Raman study.

The fully oxidized complex of cytochrome c and cytochrome oxidase formed at low ionic strength was studied by resonance Raman spectroscopy. The spectra of the complex and of the individual components were compared over a wide frequency range using Soret band excitation. In both partners of the complex, structural changes occur in the heme groups and in their immediate protein environment. The spectra of the complex in the 1600-1700 cm-1 frequency range were dominated by bands from the cytochrome oxidase component, whereas those in the 300-500 cm-1 range were dominated by bands from the cytochrome c component, hence allowing separation of the contributions from the two individual species. For cytochrome c, spectral changes were observed which correspond to the induction of the conformational state I and the six-coordinated low-spin configuration of state II on binding to cytochrome oxidase. While in state I the structure of cytochrome c is essentially the same as in solution, state II is characterized by a structural rearrangement of the heme pocket, leading to a weakening of the axial iron-methionine bond and an opening of the heme crevice which is situated in the center of the binding domain for cytochrome oxidase. The relative contributions of the two cytochrome c states were estimated to be approximately in the ratio 1:1 in the complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Mycobacterium tuberculosis 16-kDa antigen (Hsp16.3) functions as an oligomeric structure in vitro to suppress thermal aggregation.

Tuberculosis continues to be a major disease threatening millions of lives worldwide. Several antigens of Mycobacterium tuberculosis, identified by monoclonal antibodies, have been cloned and are being exploited in the development of improved vaccines and diagnostic reagents. We have expressed and purified the 16-kDa antigen, an immunodominant antigen with serodiagnostic value, which has been previously cloned and shown to share low sequence homology with the alpha-crystallin-related small heat shock protein family. Sedimentation equilibrium analytical ultracentrifugation and dynamic light scattering demonstrate the formation of a specific oligomer, 149 +/- 8 kDa, consisting of approximately nine monomers. In 4 M urea, a smaller oligomer of 47 +/- 6 kDa (or trimer) is produced. Analysis by electron cryomicroscopy reveals a triangular shaped oligomeric structure arising from the presence of three subparticles or globules. Taken together, the data suggest an antigen complex structure of a trimer of trimers. This antigen, independent of ATP addition, effectively suppresses the thermal aggregation of citrate synthase at 40 degrees C, indicating that it can function as a molecular chaperone in vitro. A complex between the antigen and heat-denatured citrate synthase can be detected and isolated using high performance liquid chromatography. We propose to rename the 16-kDa antigen Hsp16.3 to be consistent with other members of the small heat shock protein family.

Bacterial Proteins↗
PubMed1997

Three-dimensional solution structure of the complex of alpha-bungarotoxin with a library-derived peptide.

The solution structure of the complex between alpha-bungarotoxin (alpha-BTX) and a 13-residue library-derived peptide (MRYYESSLKSYPD) has been solved using two-dimensional proton-NMR spectroscopy. The bound peptide adopts an almost-globular conformation resulting from three turns that surround a hydrophobic core formed by Tyr-11 of the peptide. The peptide fills an alpha-BTX pocket made of residues located at fingers I and II, as well as at the C-terminal region. Of the peptide residues, the largest contact area is formed by Tyr-3 and Tyr-4. These findings are in accord with the previous data in which it had been shown that substitution of these aromatic residues by aliphatic amino acids leads to loss of binding of the modified peptide with alpha-BTX. Glu-5 and Leu-8, which also remarkably contribute to the contact area with the toxin, are present in all the library-derived peptides that bind strongly to alpha-BTX. The structure of the complex may explain the fact that the library-derived peptide binds alpha-BTX with a 15-fold higher affinity than that shown by the acetylcholine receptor peptide (alpha185-196). Although both peptides bind to similar sites on alpha-BTX, the latter adopts an extended conformation when bound to the toxin [Basus, V., Song, G. & Hawrot, E. (1993) Biochemistry 32, 12290-12298], whereas the library peptide is nearly globular and occupies a larger surface area of alpha-BTX binding site.

Amino Acid Sequence↗
PubMed1982

Heterogeneity of asparagine-linked oligosaccharides of five glycosylation sites on immunoglobulin M heavy chain from mineral oil plasmacytoma 104E.

Mouse myeloma immunoglobulin IgM heavy chains were cleaved with cyanogen bromide into nine peptide fragments, four of which contain asparagine-linked sites of glycosylation. Three of these glycopeptides contain a single site located at asparagines 171, 403, and 563 in the sequence of the intact heavy chain. Another glycopeptide contains two sites of glycosylation at asparagines 332 and 364. All sites contain multiple oligosaccharide structures with a trend towards increased processing from the COOH to the NH2 terminus. Structures present at asparagine 563, located only exclusively high mannose oligosaccharides. Asparagine 403, located penultimate to the COOH terminus, has a major component that is of a complex nature but is incompletely processed. Other sites contain predominantly complex structures consisting of biantennary or triantennary branches. The unusual structure found at asparagine 403 contains fucose even though only one branch has been processed to a terminal galactose. These studies suggest that each site has a unique set of heterogeneous oligosaccharides derived from a complex processing system which utilizes a combination of "position completeness" and polypeptide structure to determine final carbohydrate structure.

Amino Acid Sequence↗
PubMed1996

Evidence for two catalytically independent clusters of active sites in a functional modular polyketide synthase.

Modular polyketide synthases (PKSs), such as the 6-deoxyerythronolide B synthase (DEBS), catalyze the biosynthesis of structurally complex and medicinally important natural products. These large multifunctional enzymes are organized into "modules", where each module contains active sites homologous to those of higher eucaryotic fatty acid synthases (FASs). Like FASs, modular PKSs are known to be dimers. Here we provide functional evidence for the existence of two catalytically independent clusters of active sites within a modular PKS. In three bimodular derivatives of DEBS, the ketosynthase domain of module 1 (KS-1) or module 2 (KS-2) or the acyl carrier protein domain of module 2 (ACP-2) was inactivated via site-directed mutagenesis. As expected, the purified proteins were unable to catalyze polyketide synthesis (although the KS-1 mutant could convert a diketide thioester into the predicted triketide lactone). Remarkably however, the KS-1/KS-2 and the KS-2/ACP-2 mutant pairs could efficiently complement each other and catalyze polyketide formation. In contrast, the KS-1 and ACP-2 mutants did not complement each other. On the basis of these and other results, a model is proposed in which the individual modules of a PKS dimer form head-to-tail homodimers, thereby generating two equivalent and independent clusters of active sites for polyketide biosynthesis. Specifically, each subunit contributes half of the KS and ACP domains in each cluster. A similar complementation approach should also be useful in dissecting the organization of the remaining types of active sites within this family of multienzyme assemblies. Finally, blocked systems, such as the KS-1 mutant described here, present a new strategy for the noncompetitive conversion of unnatural substrates into polyketides by modular PKSs.

Acyl Carrier Protein↗
PubMed1999

Structure of adenovirus complexed with its internalization receptor, alphavbeta5 integrin.

The three-dimensional structure of soluble recombinant integrin alphavbeta5 bound to human adenovirus types 2 and 12 (Ad2 and -12) has been determined at approximately 21-A resolution by cryoelectron microscopy (cryo-EM). The alphavbeta5 integrin is known to promote Ad cell entry. Cryo-EM has shown that the integrin-binding RGD (Arg-Gly-Asp) protrusion of the Ad2 penton base protein is highly mobile (P. L. Stewart, C. Y. Chiu, S. Huang, T. Muir, Y. Zhao, B. Chait, P. Mathias, and G. R. Nemerow, EMBO J. 16:1189-1198, 1997). Sequence analysis indicated that the Ad12 RGD surface loop is shorter than that of Ad2 and probably less flexible, hence more suitable for structural characterization of the Ad-integrin complex. The cryo-EM structures of the two virus-receptor complexes revealed a ring of integrin density above the penton base of each virus serotype. As expected, the integrin density in the Ad2 complex was diffuse while that in the Ad12 complex was better defined. The integrin consists of two discrete subdomains, a globular domain with an RGD-binding cleft approximately 20 A in diameter and a distal domain with extended, flexible tails. Kinetic analysis of Ad2 interactions with alphavbeta5 indicated approximately 4.2 integrin molecules bound per penton base at close to saturation. These results suggest that the precise spatial arrangement of five RGD protrusions on the penton base promotes integrin clustering and the signaling events required for virus internalization.

Adenoviruses, Human↗
PubMed1999

NMR solution structure of a complex of calmodulin with a binding peptide of the Ca2+ pump.

The three-dimensional structure of the complex between calmodulin (CaM) and a peptide corresponding to the N-terminal portion of the CaM-binding domain of the plasma membrane calcium pump, the peptide C20W, has been solved by heteronuclear three-dimensional nuclear magnetic resonance (NMR) spectroscopy. The structure calculation is based on a total of 1808 intramolecular NOEs and 49 intermolecular NOEs between the peptide C20W and calmodulin from heteronuclear-filtered NOESY spectra and a half-filtered experiment, respectively. Chemical shift differences between free Ca(2+)-saturated CaM and its complex with C20W as well as the structure calculation reveal that C20W binds solely to the C-terminal half of CaM. In addition, comparison of the methyl resonances of the nine assigned methionine residues of free Ca(2+)-saturated CaM with those of the CaM/C20W complex revealed a significant difference between the N-terminal and the C-terminal domain; i.e., resonances in the N-terminal domain of the complex were much more similar to those reported for free CaM in contrast to those in the C-terminal half which were significantly different not only from the resonances of free CaM but also from those reported for the CaM/M13 complex. As a consequence, the global structure of the CaM/C20W complex is unusual, i.e., different from other peptide calmodulin complexes, since we find no indication for a collapsed structure. The fine modulation in the peptide protein interface shows a number of differences to the CaM/M13 complex studied by Ikura et al. [Ikura, M., Clore, G. M., Gronenborn, A. M., Zhu, G., Klee, C. B., and Bax, A. (1992) Science 256, 632-638]. The unusual binding mode to only the C-terminal half of CaM is in agreement with the biochemical observation that the calcium pump can be activated by the C-terminal half of CaM alone [Guerini, D., Krebs, J., and Carafoli, E. (1984) J. Biol. Chem. 259, 15172-15177].

Amino Acid Sequence↗
PubMed1993

Anthracycline-DNA interactions at unfavourable base-pair triplet-binding sites: structures of d(CGGCCG)/daunomycin and d(TGGCCA)/adriamycin complexes.

The structures of two hexanucleotide-anthracycline complexes d(CGGCCG)/daunomycin and d(TGGCCA)/adriamycin have been determined using single-crystal X-ray diffraction techniques. In both cases the anthracycline molecule is bound to non-preferred d(YGG) base-pair triplet sites. For both complexes the crystals are tetragonal and belong to the space group P4(1)2(1)2. Unit-cell dimensions are a = 28.07 (2), c = 53.35 (1) and a = 28.01 (1), c = 52.99 (1) A, respectively, and the asymmetric unit of both structures consists of one strand of DNA, one drug molecule and approximately 50 water molecules. For the d(CGGCCG) complex the refinement converged with an R factor of 0.21 for 1108 reflections with F >/= 2sigma(F) in the resolution range 7.0-1.9 A. For the complex involving d(TGGCCA) the final R value was 0.22 for 1475 reflections in the range 7.0-1.7 A with the same criterion for observed data. Both complexes are essentially isomorphous with related structures but differ in terms of the number of favourable van der Waals interactions of the amino sugars of the drug molecules with the DNA duplexes and the formation in the minor groove of heterodromic pentagonal arrangements of hydrogen bonds involving water molecules which link the amino sugars to the DNA. These differences in structure are used to rationalize the lack of affinity of daunomycin-type anthracyclines for d(YGG) and d(YGC) sites.

Journal Article↗
PubMed1998

The solution structure of the complex of Lactobacillus casei dihydrofolate reductase with methotrexate.

We have determined the three-dimensional solution structure of the complex of Lactobacillus casei dihydrofolate reductase (18.3 kDa, 162 amino acid residues) formed with the anticancer drug methotrexate using 2531 distance, 361 dihedral angle and 48 hydrogen bond restraints obtained from analysis of multidimensional NMR spectra. Simulated annealing calculations produced a family of 21 structures fully consistent with the constraints. The structure has four alpha-helices and eight beta-strands with two other regions, comprising residues 11 to 14 and 126 to 127, also interacting with each other in a beta-sheet manner. The methotrexate binding site is very well defined and the structure around its glutamate moiety was improved by including restraints reflecting the previously determined specific interactions between the glutamate alpha-carboxylate group with Arg57 and the gamma-carboxylate group with His28. The overall fold of the binary complex in solution is very similar to that observed in the X-ray studies of the ternary complex of L. casei dihydrofolate reductase formed with methotrexate and NADPH (the structures of the binary and ternary complexes have a root-mean-square difference over the backbone atoms of 0.97 A). Thus no major conformational change takes place when NADPH binds to the binary complex. In the binary complex, the loop comprising residues 9 to 23 which forms part of the active site has been shown to be in the "closed" conformation as defined by M. R. Sawaya & J. Kraut, who considered the corresponding loops in crystal structures of complexes of dihydrofolate reductases from several organisms. Thus the absence of the NADPH does not result in the "occluded" form of the loop as seen in crystal studies of some other dihydrofolate reductases in the absence of coenzyme. Some regions of the structure in the binary complex which form interaction sites for NADPH are less well defined than other regions. However, in general terms, the NADPH binding site appears to be essentially pre-formed in the binary complex. This may contribute to the tighter binding of coenzyme in the presence of methotrexate.

Binding Sites↗
PubMed2005

Seismological constraints on a possible plume root at the core-mantle boundary.

Recent seismological discoveries have indicated that the Earth's core-mantle boundary is far more complex than a simple boundary between the molten outer core and the silicate mantle. Instead, its structural complexities probably rival those of the Earth's crust. Some regions of the lowermost mantle have been observed to have seismic wave speed reductions of at least 10 per cent, which appear not to be global in extent. Here we present robust evidence for an 8.5-km-thick and approximately 50-km-wide pocket of dense, partially molten material at the core-mantle boundary east of Australia. Array analyses of an anomalous precursor to the reflected seismic wave ScP reveal compressional and shear-wave velocity reductions of 8 and 25 per cent, respectively, and a 10 per cent increase in density of the partially molten aggregate. Seismological data are incompatible with a basal layer composed of pure melt, and thus require a mechanism to prevent downward percolation of dense melt within the layer. This may be possible by trapping of melt by cumulus crystal growth following melt drainage from an anomalously hot overlying region of the lowermost mantle. This magmatic evolution and the resulting cumulate structure seem to be associated with overlying thermal instabilities, and thus may mark a root zone of an upwelling plume.

Journal Article↗
PubMed1994

A structural basis for the interaction of urea with lysozyme.

The effect of urea on the crystal structure of hen egg-white lysozyme has been investigated using X-ray crystallography. High resolution structures have been determined from crystals grown in the presence of 0, 0.7, 2, 3, 4, and 5 M urea and from crystals soaked in 9 M urea. All the forms are essentially isomorphous with the native type II crystals, and the derived structures exhibit excellent geometry and RMS differences from ideality in bond distances and angles. Comparison of the urea complex structures with the native enzyme (type II form, at 1.5 A resolution) indicates that the effect of urea is minimal over the concentration range studied. The mean difference in backbone conformation between the native enzyme and its urea complexes varies from 0.18 to 0.49 A. Conformational changes are limited to flexible surface loops (Thr 69-Asn 74, Ser 100-Asn 103), the active site loop (Asn 59-Cys 80), and the C-terminus (Cys 127-Leu 129). Urea molecules are bound to distinct sites on the surface of the protein. One molecule is bound to the active site cleft's C subsite, at all concentrations, in a fashion analogous to that of the N-acetyl substituent of substrate and inhibitor sugars normally bound to this site. Occupation of this subsite by urea alone does not appear to induce the conformational changes associated with inhibitor binding.

Amino Acid Sequence↗
PubMed2000

Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions.

Multistep chemical reactions are increasingly seen as important in a growing number of complex biotransformations. Covalently attached prosthetic groups or swinging arms, and their associated protein domains, are essential to the mechanisms of active-site coupling and substrate channeling in a number of the multifunctional enzyme systems responsible. The protein domains, for which the posttranslational machinery in the cell is highly specific, are crucially important, contributing to the processes of molecular recognition that define and protect the substrates and the catalytic intermediates. The domains have novel folds and move by virtue of conformationally flexible linker regions that tether them to other components of their respective multienzyme complexes. Structural and mechanistic imperatives are becoming apparent as the assembly pathways and the coupling of multistep reactions catalyzed by these dauntingly complex molecular machines are unraveled.

Animals↗
PubMed2005

[A discussion on the CSP genotyping of Plasmodium vivax and malaria control in five southern provinces of China].

OBJECTIVE: To explore circumsporozoite protein (CSP) genotype structure of Plasmodium vivax in southern China and evaluate its epidemiological significance. METHODS: Filter paper blood samples were collected from 346 vivax malaria patients in 5 provinces (Autonomous Region) including Hainan, Yunnan, Guangxi, Guangdong and Guizhou for identifying CSP genotypes, by using the method of single-tube nested/multiplex PCR. The findings combined with relevant data were statistically analyzed. RESULTS: In Guangdong, Guangxi and Guizhou Provinces (Autonomous Region), the temperate zone family strains accounted for more than 90%, with only a few tropical zone family strains and no PV-type II each strain. In Yunnan Province, temperate strains and tropical strains accounted for 71.4% and 28.6% respectively, with occasional PV-type II strain. In Hainan Province, strains of temperate zone, tropical zone and PV-type II accounted for about one-third. CONCLUSIONS: The temperate zone family strains were the predominant ones in the Provinces (Autonomous Region) of Guangdong, Guangxi and Guizhou where malaria control was carried out effectively; while in Hainan and Yunnan Provinces the difficulties in malaria control may probably be related to the complex structure of P. vivax population and multiple infections of different genotypes. The findings indicate that the complexity of the P. vivax genotype structure might be an indicative epidemiological feature for malaria control and surveillance.

Animals↗
PubMed2004

Effect of heterogeneous structure in mechanically unstressed biofilms on overall growth.

In contrast to their name, biofilms are not always flat and homogeneous but instead often exhibit complex structural heterogeneity. It has been suggested that nonhomogeneous geometry is selected in order to increase biofilm growth rate. A previous study (Dockery and Klapper (2002) SIAM J. Appl. Math., 62, 853-869) of a model biofilm system in a static bulk fluid demonstrated that under some circumstances a flat biofilm-bulk fluid interface is linearly unstable to perturbation due to growth induced forces. Computations indicated that subsequent nonlinear evolution results in fingers and mushrooms of biofilm similar to structures observed in actual biofilms. However, the important complementary issue of biological functionality was not considered. Here a weakly nonlinear analysis of the simple growing biofilm layer model in Dockery and Klapper (2002, SIAM J. Appl. Math., 62, 853-869) is presented. It is argued that, at least in the case of biofilms free of external mechanical stress, overall growth is in fact generally inhibited by the presence of growing perturbations in the linear stage. Hence a more complex explanation of function is necessary.

Biofilms↗
PubMed1994

The structure of a complex between the NC10 antibody and influenza virus neuraminidase and comparison with the overlapping binding site of the NC41 antibody.

BACKGROUND: While it is well known that different antibodies can be produced against a particular antigen, and even against a particular site on an antigen, up until now there have been no structural studies of cross-reacting antibodies of this type. One antibody-antigen complex whose structure is known is that of the influenza virus antigen, neuraminidase, in complex with the NC41 antibody. Another anti-neuraminidase antibody, NC10, binds to an overlapping site on the antigen. The structure of the complex formed by this antibody with neuraminidase is described here and compared with the NC41-containing complex. RESULTS: The crystal structure of the NC10 Fab-neuraminidase complex has been refined to a nominal resolution of 2.5A. Approximately 80% of the binding site of the NC10 antibody on neuraminidase overlaps with that of the NC41 antibody. The epitope residues of neuraminidase are often engaged in quite different interactions with the two antibodies. Although the NC10 and NC41 antibodies have identical amino acid sequences within the first complementarity determining region of their heavy chains, this is not the basis of the cross-reaction. CONCLUSIONS: The capacity of two different proteins to bind to the same target structure on a third protein need not be based on the existence of identical or homologous amino acid sequences within those proteins. As we have demonstrated, amino acid residues on the common target structure may be in quite different chemical environments, and may also adopt different conformations within two protein-protein complexes.

Amino Acid Sequence↗