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PubMed1998

Recognition of RNase Sa by the inhibitor barstar: structure of the complex at 1.7 A resolution.

We report the 1.7 A resolution structure of RNase Sa complexed with the polypeptide inhibitor barstar. The crystals are in the hexagonal space group P65 with unit-cell dimensions a = b = 56.9, c = 135.8 A and the asymmetric unit contains one molecule of the complex. RNase Sa is an extracellular microbial ribonuclease produced by Streptomyces aureofaciens. Barstar is the natural inhibitor of barnase, the ribonuclease of Bacillus amyloliquefaciens. It inhibits RNase Sa and barnase in a similar manner by steric blocking of the active site. The structure of RNase Sa is very similar to that observed in crystals of the native enzyme and its complexes with nucleotides. Barstar retains the structure found in its complex with barnase. The accessible surface area of protein buried in the complex is about 300 A2 smaller and there are fewer hydrogen bonds in the enzyme-inhibitor interface in RNase Sa-barstar than in barnase-barstar, providing an explanation of the reduced binding affinity in the former. Previous studies of barstar complexes have used mutants of the inhibitor and this is the first structure which includes wild-type barstar.

Amino Acid Sequence↗
PubMed1995

Synthesis of (+)-dynemicin A and analogs of wide structural variability: establishment of the absolute configuration of natural dynemicin A.

BACKGROUND: Dynemicin A is an exceedingly potent antitumor antibiotic derived from microbial fermentation that cleaves double-stranded B-form DNA in vitro in the presence of activating factors such as NADPH or glutathione. Because of the structural complexity, high reactivity, and scarcity of natural dynemicin A, it has not been feasible to modify the structure to any significant extent. Previous studies have not determined the absolute configuration of the natural product. RESULTS: A multistep route for the preparation of enantiomerically pure, synthetic dynemicin A was developed. The absolute configuration of natural dynemicin was determined by comparing the synthetic drug with dynemicin A derived from fermentation. The route that was developed is highly convergent, as the result of a late-stage coupling reaction that combines two complex synthetic fragments, and has been shown to provide access to non-natural dynemicins of wide structural variability by modifications of these fragments. In this way, several nonnatural dynemicins, unavailable by any other means, were synthesized and shown to have DNA-cleaving activity in the presence of glutathione or NADPH. CONCLUSIONS: Enantiomerically pure dynemicin A is now available by laboratory synthesis. The natural, (+)-enantiomer of dynemicin A is shown to possess the 2S, 3S, 4S, 7R, 8R configuration. A wide variety of heretofore unavailable, active analogs of dynemicin A have been prepared and are found to produce subtle variations in sequence specificity of DNA cleavage compared to the natural product and, of potentially greater significance, display variations in the efficiency of DNA cleavage as a function of the activating agent.

Anthraquinones↗
PubMed2006

Molecular wiring of nanocrystals: NCS-enhanced cross-surface charge transfer in self-assembled Ru-complex monolayer on mesoscopic oxide films.

We report on rapid ambipolar cross-surface charge transfer within self-assembled monolayers (SAM) of the heteroleptic Ru-complexes cis-RuLL'(NCS)(2) (L = 2,2'-bipyridyl-4,4'-dicarboxylic acid, L' = 4,4'-dinonyl-2,2'-bipyridyl) (1) and cis-RuLL' '(NCS)(2) (L = 2,2'-bipyridyl-4,4'-dicarboxylic acid, L' = 4,4'-dimethyl-2,2'-bipyridyl) (2) on the surface of mesoscopic insulating oxide films. The bipyridyl ligands of the Ru-complex transport electrons, while the NCS groups plays a pivotal role in mediating surface confined hole percolation. Molecular dynamics calculations show the NCS ligands of 1 and 2 to orient in a fashion that enhances the overlap of the HOMOs of neighboring ruthenium complexes. Using ab initio Hartree-Fock calculations the electronic coupling matrix element for intermolecular hole exchange at the surface is estimated to be 0.13 eV. Cyclic voltammetry as well as spectroelectrochemical and impedance measurements performed with a series of other Ru-complexes confirmed the control of the cross surface charge transfer by the molecular structure. Complex 2 shows the highest percolation rate, the surface hole diffusion coefficient being 1.1 x 10(-8) cm(2)/s. The effects of the ligand properties, such as denticity, geometry, and size, on the intermolecular charge transport are discussed in detail.

Journal Article↗
PubMed2006

Facile fabrication of microfluidic systems using electron beam lithography.

We present two fast and generic methods for the fabrication of polymeric microfluidic systems using electron beam lithography: one that employs spatially varying electron-beam energy to expose to different depths a negative electron-beam resist, and another that employs a spatially varying electron-beam dose to differentially expose a bi-layer resist structure. Using these methods, we demonstrate the fabrication of various microfluidic unit structures such as microchannels of a range of geometries and also other more complex structures such as a synthetic gel and a chaotic mixer. These are made without using any separate bonding or sacrificial layer patterning and etching steps. The schemes are inherently simple and scalable, afford high resolution without compromising on speed and allow post CMOS fabrication of microfluidics. We expect them to prove very useful for the rapid prototyping of complete integrated micro/nanofluidic systems with sense and control electronics fabricated by upstream processes.

Electrons↗
PubMed2003

Can potentially useful dynamics to solve complex problems emerge from constrained chaos and/or chaotic itinerancy?

Complex dynamics including chaos in systems with large but finite degrees of freedom are considered from the viewpoint that they would play important roles in complex functioning and controlling of biological systems including the brain, also in complex structure formations in nature. As an example of them, the computer experiments of complex dynamics occurring in a recurrent neural network model are shown. Instabilities, itinerancies, or localization in state space are investigated by means of numerical analysis, for instance by calculating correlation functions between neurons, basin visiting measures of chaotic dynamics, etc. As an example of functional experiments with use of such complex dynamics, we show the results of executing a memory search task which is set in a typical ill-posed context. We call such useful dynamics "constrained chaos," which might be called "chaotic itinerancy" as well. These results indicate that constrained chaos could be potentially useful in complex functioning and controlling for systems with large but finite degrees of freedom typically observed in biological systems and may be such that working in a delicate balance between converging dynamics and diverging dynamics in high dimensional state space depending on given situation, environment and context to be controlled or to be processed.

Journal Article↗
PubMed2003

Crystal structures of threonine synthase from Thermus thermophilus HB8: conformational change, substrate recognition, and mechanism.

Threonine synthase, which is a PLP-dependent enzyme, catalyzes the beta,gamma-replacement reaction of l-homoserine phosphate to yield threonine and inorganic phosphate. The three-dimensional structures of the enzyme from Thermus thermophilus HB8 in its unliganded form and complexed with the substrate analogue 2-amino-5-phosphonopentanoic acid have been determined at 2.15 and 2.0 A resolution, respectively. The complexed form, assigned as an enamine, uncovered the interactions of the cofactor-analogue conjugate with the active site residues. The binding of the substrate analogue induces a large conformational change at the domain level. The small domain rotates by about 25 degrees and approaches the large domain to close the active site. The complicated catalytic process of the enzyme has been elucidated based on the complex structure to reveal the stereochemistry of the reaction and to present the released inorganic phosphate as a possible catalyst to carry a proton to the Cgamma atom of the substrate.

Binding Sites↗
PubMed2001

Constructing a Golgi complex.

In this issue, Short et al. report the discovery of a protein named Golgin-45 that is located on the surface of the middle (or medial) cisternae of the Golgi complex. Depletion of this protein disrupts the Golgi complex and leads to the return of a resident, lumenal, medial Golgi enzyme to the endoplasmic reticulum. These findings suggest that Golgin-45 serves as a linchpin for the maintenance of Golgi complex structure, and offer hints as to the mechanisms by which the polarized Golgi complex is constructed.

Animals↗
PubMed2001

X-LIGAND: an application for the automated addition of flexible ligands into electron density.

With the advent of drug-design experiments where the interaction between a protein and a ligand is determined using X-ray crystallography, the use of automated methods for modelling the ligand into electron density represents a powerful tool. Once the protein structure has been determined by crystallography it is normal that subsequent ligand-complex structures are isomorphous, or nearly so, with the original structure and it is necessary only to determine the fit of ligand to any unsatisfied electron density. The X-LIGAND application was designed with this protocol in mind and provides a tool that searches for unsatisfied electron density and then fits flexible ligands to this within minutes without user intervention.

Automation↗
PubMed1998

Molecular replacement: the revival of the molecular Fourier transform method.

The molecular Fourier transform method, perhaps the first application of the molecular-replacement approach, used in the 1950s for the two-dimensional structure determination of small molecules, has been modernised for the efficient solution of complex structures. In the modern application of the molecular Fourier transform (MFT), the three-dimensional transform of the molecular model is calculated and fitting is achieved by rotating the weighted reciprocal lattice with respect to the calculated transform. The fit between the transform and the weighted reciprocal lattice is gauged by three different criteria corresponding to R factor, correlation coefficient and product function. Since the procedure involves the rotation of indices and is, therefore, independent of the number of atoms, it is much faster than other methods which employ the rotation of the molecular model. This feature enabled the renovation of the rotation-translation search method ULTIMA, which utilizes low-order data and packing considerations for the efficient solution of large structures.

Alcohol Dehydrogenase↗
PubMed1998

Model-guided labeling of coronary structure.

Assigning anatomic labels to coronary arteries in X-ray angiograms is an important task in medical imaging, motivated by the desire to standardize the assessment of coronary artery disease and to facilitate the three-dimensional (3-D) reconstruction and visualization of the coronary vasculature. However, automatic labeling poses a number of significant challenges, including the presence of noise, artifacts, competing structures, misleading visual cues, and other difficulties associated with a dynamic and inherently complex structure. We have developed a model-guided approach that addresses these challenges and automatically labels the vascular structure in coronary angiographic images. The approach consists of two models: 1) a symbolic model, represented through a directed acyclic graph, that captures vascular tree hierarchies and branch interrelationships and 2) a generalized 3-D model that captures spatial and geometric relationships. Importantly, the approach detects ambiguities (such as vessel overlaps) that may be found in a frame of a ciné sequence, and resolves these ambiguities by considering the information derived from other (unambiguous) frames in the temporal sequence, employing dynamic programming methods to match the image features found in the different (ambiguous and unambiguous) frames. This paper presents this model-guided labeling algorithm and discusses the experimental results obtained from implementing and applying the resulting labeling system to a variety of clinical images. The results indicate the feasibility of achieving robust and consistently accurate image labeling through this model-guided, temporal disambiguation method.

Coronary Angiography↗
PubMed2002

Finite element analysis in spine research.

Finite element analysis is a widely accepted tool used in many industries and research activities. It allows new designs to be thoroughly 'tested' before a prototype is even manufactured, components and systems which cannot readily be experimented upon to be examined, and 'diagnostic' investigations to be undertaken. Finite element models are already making an important contribution to our understanding of the spine and its components. Models are being used to reveal the biomechanical function of the spine and its behaviour when healthy, diseased or damaged. They are also providing support in the design and application of spinal instrumentation. The spine is a very complex structure, and many of the models are simplified and idealized because of the complexity and uncertainty in the geometry, material properties and boundary conditions of these problems. This type of modelling simplification is not peculiar to spinal modelling problems. Indeed, the idealization is often a strength when there is such uncertainty and variation between one individual and another, allowing cause-effect relationships to be isolated and fully explored, and the inherent variability of experimental tests to be eliminated. This paper reviews the development of finite element analysis in spinal modelling. It shows how modelling provides a wealth of information on our physiological performance, reduces our dependence on animal and cadaveric experiments and is an invaluable complement to clinical studies. It also leads to the conclusion that, as computing power and software capabilities increase, it is quite conceivable that in the future it will be possible to generate patient-specific models that could be used for patient assessment and even pre- and inter-operative planning.

Biomechanical Phenomena↗
PubMed1988

Anatomy and biomechanics of the anterior cruciate ligament.

The ACL is an important living soft-tissue component of ancient origin that acts in combination with other complex structures to provide control of femorotibial kinematics. The effect on the knee of its loss, resulting in disruptive kinematics and often subsequent degenerative changes, probably occurs not only because of its lack of structural integrity but also perhaps because of disruption of its proprioceptive function. The complexity of this ligament and associated normal kinematics of the knee challenges the ability of orthopaedists to devise effective therapeutic measures to reconstitute its function when lost. A clearer understanding of the normal role of the ACL will aid in this effort.

Biomechanical Phenomena↗
PubMed1980

The morphology of the diencephalon in the Prosimii. II. The Lemuroidea and Lorisoidea. Part I. Thalamus and metathalamus.

This study (Part I) covers the comparative structure of the thalamus and metathalamus in the prosimian superfamilies, Lorisoidea and Lemuroidea. Several lemuroid specimens, namely Lemus, Cheirogaleus, Microcebus, Avahi and Daubentonia, and lorisoid specimens such as Galago, Perodicticus and Loris have been used in this extensive study. The anterior nuclear group does not show much difference among these species, although attention is focussed on the differentiation of the principal anterior nucleus into anteromedial and anteroventral parts; the latter increases in structural complexity. The anterodorsal nucleus has regressed into a small, flattened cap-line structure covering the dorsal surface of the anteroventral nucleus. The midline thalamic nuclei are more or less the same throughout the entire prosimian primate scale, though the gradual fusion of the nucleus rhomboidalis with the nucleus centralis medialis is observed from Microcebus to Daubentonia. The medial thalamic nuclear region is dominated by the nucleus mediodorsalis which is clearly differentiated into dorsomedial magnocellular and ventrolateral parvocellular protions. A third division consisting of rather large, darkly staining cells have been observed in the caudal region of the nucleus mediodorsalis. The nuclei centrum medianum and parafascicularis are both large in size, but is not completely demarcated from each other. The dorsolateral thalamic nuclei--the nuclei laterales dorsalis, intermedius and posterior, are well developed, but cannot be distinguished from one another. The pulvinar shows a remarkable phylogenetic development; it does not only enlarge, but is differentiated into several distinct parts. The ventrolateral thalamic nuclear group is comparably larger in structural size than the dorsolateral thalamic nuclei. The nuclei ventrales anterior and lateralis are not clearly demarcated from each other, but on both cyto- and myelo-architectonic grounds, are separate entities. The nucleus ventralis posterior is differentiated into lateral, medial and inferior parts. The posterior thalamic nuclei show the beginnings of regression. The nucleus pretectalis remains comparatively large in size and divided into medial and lateral parts. The nucleus posterior thalamicus is either absent or involuted into other nuclei. The nucleus limitans makes its first appearance in the Prosimii. The lateral geniculate body is very variable in size in all respects among the prosimian species, that is, in the dorsoventral shift along the lateral surface of the thalamus, the cellular differentiation of the lateral geniculate nucleus into 5 or 6 layers, the topographical position of the pregeniculate nucleus and the degree of inversion. The medial geniculate body is shown to be clearly subdivided on cyto-architectonic grounds into dorsomedial and ventrolateral parts; a magnocellular protion can be seen on the dorsal region of this nucleus, and appears to be closely related to the nucleus suprageniculatus.

Animals↗
PubMed2002

A compact RNA tertiary structure contains a buried backbone-K+ complex.

The structure of a 58 nucleotide ribosomal RNA fragment buries several phosphate groups of a hairpin loop within a large tertiary core. During refinement of an X-ray crystal structure containing this RNA, a potassium ion was found to be contacted by six oxygen atoms from the buried phosphate groups; the ion is contained completely within the solvent-accessible surface of the RNA. The electrostatic potential at the ion chelation site is unusually large, and more than compensates for the substantial energetic penalties associated with partial dehydration of the ion and displacement of delocalized ions. The very large predicted binding free energy, approximately -30 kcal/mol, implies that the site must be occupied for the RNA to fold. These findings agree with previous studies of the ion-dependent folding of tertiary structure in this RNA, which concluded that a monovalent ion was bound in a partially dehydrated environment where Mg2+ could not easily compete for binding. By compensating the unfavorable free energy of buried phosphate groups with a chelated ion, the RNA is able to create a larger and more complex tertiary fold than would be possible otherwise.

Base Sequence↗
PubMed2005

The mechanism of Mo-/Cu-dependent CO dehydrogenase.

Density functional theory computations at the B3LYP/SDDp//B3LYP/Lanl2DZ level were performed on model complexes derived from [(Me(2)C(2)S(2))Mo(O)(2)-S-CuSMe](2-) or its oxo protonated form to gain insight into the reaction steps involved in substrate oxidation of a Mo-/Cu-dependent CO dehydrogenase. Only the bisoxo but not the hydroxo oxo complex was found to oxidize CO exothermically. A thiocarbamate complex structurally characterized as the reaction product of the enzyme with the inhibitor n-butylisonitrile corresponds to a thermodynamic well on the potential energy surface. For the formation of the analogous thiocarbonate complex from CO oxidation, however, we do not find a significant thermodynamic driving force. In the protein matrix of the enzyme this species should be further destabilized, as it requires the metal centers to move apart considerably from each other.

Aldehyde Oxidoreductases↗
PubMed2003

Biochemical filtering of a protein-protein docking simulation identifies the structure of a complex between a recombinant antibody fragment and alpha-bungarotoxin.

The structural characterization of a complex of alpha-bungarotoxin with a recombinant antibody fragment that mimics the acetylcholine receptor was achieved using docking simulation procedures. To drive the computer simulation towards a limited set of solutions with biological significance, a filter, incorporating general considerations of antigen-antibody interactions, specificity of the selected antibody fragment and results from alpha-bungarotoxin epitope mapping, was adopted. Two similar structures were obtained for the complex, both of them stabilized by cation-pi and hydrophobic interactions due to tyrosilyl residues of the antibody fragment. Site-directed mutagenesis studies, removing each of the latter aromatic residues and causing full inactivation of the interaction process between the antibody fragment and the neurotoxin, support the validity of the calculated structure of the complex.

Amino Acid Sequence↗
PubMed2005

A heterodimeric complex that promotes the assembly of mammalian 20S proteasomes.

The 26S proteasome is a multisubunit protease responsible for regulated proteolysis in eukaryotic cells. It comprises one catalytic 20S proteasome and two axially positioned 19S regulatory complexes. The 20S proteasome is composed of 28 subunits arranged in a cylindrical particle as four heteroheptameric rings, alpha1-7beta1-7beta1-7alpha1-7 (refs 4, 5), but the mechanism responsible for the assembly of such a complex structure remains elusive. Here we report two chaperones, designated proteasome assembling chaperone-1 (PAC1) and PAC2, that are involved in the maturation of mammalian 20S proteasomes. PAC1 and PAC2 associate as heterodimers with proteasome precursors and are degraded after formation of the 20S proteasome is completed. Overexpression of PAC1 or PAC2 accelerates the formation of precursor proteasomes, whereas knockdown by short interfering RNA impairs it, resulting in poor maturation of 20S proteasomes. Furthermore, the PAC complex provides a scaffold for alpha-ring formation and keeps the alpha-rings competent for the subsequent formation of half-proteasomes. Thus, our results identify a mechanism for the correct assembly of 20S proteasomes.

Animals↗
PubMed1980

Magnetic circular dichroism on oxygen complexes of hemoproteins: correlation between magnetic circular dichroism magnitude and electronic structures of oxygen complexes.

Magnetic circular dichroism (MCD) and natural circular dichroism (CD) spectra are reported for horseradish peroxidase Compounds II and III, and kangaroo myoglobin Compound II at pH values of 8.5 and 4.9. These compounds exhibited MCD spectra of apparent Faraday A term both in the Soret and Q regions, except for myoglobin compounds in the Soret region where intrinsic temperature dependence showed large contribution from Faraday C terms. Comparison of these data with the MCD spectra of the dioxygen complexes of hemoglobin (myoglobin) and cytochrome P-450 revealed that the magnitude of the apparent Faraday A term trough at the Q0-0 bands decreased in the order of O2 complexes of hemoglobin (myoglobin) ([theta]M not equal to 16) greater than horseradish peroxidase Compound III ([theta]M not equal to 8) greater than O2 complex of cytochrome P-450 ([theta]M not equal to 4). The [theta]M values of the oxygen complex of cytochrome P-450 is similar to those observed for the compounds II of horseradish peroxidase and kangaroo myoglobin. From these observations it was concluded that the magnitude of MCD, especially the trough depth of the Q0-0 band, has direct correlation to the electronic states of the oxygen complexes of the hemoproteins. The implication of the findings was discussed in terms of the iron electronic structures perturbed by the axial ligation.

Animals↗