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PubMed1995

Theoretical analysis of the structure of the peptide fasciculin and its docking to acetylcholinesterase.

The fasciculins are a family of closely related peptides that are isolated from the venom of mambas and exert their toxic action by inhibiting acetylcholinesterase (AChE). Fasciculins belong to the structural family of three-fingered toxins from Elapidae snake venoms, which include the alpha-neurotoxins that block the nicotinic acetylcholine receptor and the cardiotoxins that interact with cell membranes. The features unique to the known primary and tertiary structures of the fasciculin molecule were analyzed. Loop I contains an arginine at position 11, which is found only in the fasciculins and could form a pivotal anchoring point to AChE. Loop II contains five cationic residues near its tip, which are partly charge-compensated by anionic side chains in loop III. By contrast, the other three-fingered toxins show full charge compensation within loop II. The interaction of fasciculin with the recognition site on acetylcholinesterase was investigated by estimating a precollision orientation followed by determination of the buried surface area of the most probable complexes formed, the electrostatic field contours, and the detailed topography of the interaction surface. This approach has led to testable models for the orientation and site of bound fasciculin.

Acetylcholinesterase↗
PubMed1998

Kinetic epitope mapping of the chicken lysozyme.HyHEL-10 Fab complex: delineation of docking trajectories.

The rate constants, k(on), for the formation of hen (chicken) lysozyme (HEWL). Fab-10 complexes have been determined for wild-type (WT) and epitope-mutated lysozymes by a homogeneous solution method based on the 95% reduced enzymatic activity of the complex. The values fall within a narrow 10-fold range [(0.18 to 1.92) x 10(6) M(-1)s(-l)]. The affinity constants, K(D), cover a broader, 440-fold, range from 0.075 to 33 nM. Values of K(D) as high as 7 microM were obtained for the complexes prepared from some mutations at HEWL positions 96 and 97, but the associated kinetic constants could not be determined. The values of k(on) are negatively correlated with side-chain volume at position 101HEWL, but are essentially independent of this parameter for position 21HEWL substitutions. The multiple mutations made at positions 21HEWL and 101HEWL provide sufficient experimental data on complex formation to evaluate phi values [phi = (deltadeltaGon)/(deltadeltaG(D))] at these two positions to begin to define trajectories for protein-protein association. The data, when interpreted within the concept of a two-step association sequence embracing a metastable encounter complex intermediate, argue that the rate determining step at position 21HEWL (phiavg = 0.2) is encounter complex formation, but the larger phi(avg) value of 0.36 experienced for most position 101HEWL mutations indicates a larger contribution from the post-encounter annealing process at this site for these replacements.

Animals↗
PubMed2003

Protein-protein docking predictions for the CAPRI experiment.

We predicted structures for all seven targets in the CAPRI experiment using a new method in development at the time of the challenge. The technique includes a low-resolution rigid body Monte Carlo search followed by high-resolution refinement with side-chain conformational changes and rigid body minimization. Decoys (approximately 10(6) per target) were discriminated using a scoring function including van der Waals and solvation interactions, hydrogen bonding, residue-residue pair statistics, and rotamer probabilities. Decoys were ranked, clustered, manually inspected, and selected. The top ranked model for target 6 predicted the experimental structure to 1.5 A RMSD and included 48 of 65 correct residue-residue contacts. Target 7 was predicted at 5.3 A RMSD with 22 of 37 correct residue-residue contacts using a homology model from a known complex structure. Using a preliminary version of the protocol in round 1, target 1 was predicted within 8.8 A although few contacts were correct. For targets 2 and 3, the interface locations and a small fraction of the contacts were correctly identified.

Algorithms↗
PubMed2003

GAPDOCK: a Genetic Algorithm Approach to Protein Docking in CAPRI round 1.

As part of the first Critical Assessment of PRotein Interactions, round 1, we predict the structure of two protein-protein complexes, by using a genetic algorithm, GAPDOCK, in combination with surface complementarity, buried surface area, biochemical information, and human intervention. Among the five models submitted for target 1, HPr phosphocarrier protein (B. subtilis) and the hexameric HPr kinase (L. lactis), the best correctly predicts 17 of 52 interprotein contacts, whereas for target 2, bovine rotavirus VP6 protein-monoclonal antibody, the best model predicts 27 of 52 correct contacts. Given the difficult nature of the targets, these predictions are very encouraging and compare well with those obtained by other methods. Nevertheless, it is clear that there is a need for improved methods for distinguishing between "correct" and "plausible but incorrect" complexes.

Algorithms↗
PubMed1997

Docking of verapamil in a synthetic Ca2+ channel: formation of a ternary complex involving Ca2+ ions.

The mechanism by which diverse drugs modulate voltage-dependent Ca2+ channels is ill-understood. We have approached this problem by examining the interaction of verapamil with a 97-residue synthetic channel peptide (SCP) that exhibits functional similarities to authentic L-type Ca2+ channels in terms of cation selectivity and permeation as well as interaction with channel-activating and blocking drugs (Grove et al. (1991) Proc. Natl. Acad. Sci. USA 88, 6418). Different possibilities of binding of verapamil inside the Ca(2+)-bound SCP were simulated using the Monte Carlo-with-energy-minimization method. In the optimal mode of the binding, verapamil adopted a folded conformation and fit snugly in the pore. The dimethoxyphenyl groups of the drug interacted with two Ca2+ ions coordinated to the acidic residues of SCP, thus forming a ternary complex of the drug, Ca2+, and channel. The isopropyl group of verapamil abetted a ring of four Ile residues constituting the putative SCP gate. The occlusion of this gate by verapamil in this manner was strikingly similar to that accomplished by the methyl group of dihydropyridine drugs. In conjunction with an earlier study on SCP bound to dihydropyridine drugs (Zhorov and Ananthanarayanan (1996) Biophys. J. 70, 22), our data suggest that, in general, drug modulation of SCP would involve the interaction of the ligands with the pore-bound Ca2+ and with the hydrophobic gate. In light of the functional similarity between SCP and L-type Ca2+ channel, it is likely that the latter would also interact with drugs in a similar fashion.

Amino Acid Sequence↗
PubMed2002

Kinetic model of ethopropazine interaction with horse serum butyrylcholinesterase and its docking into the active site.

The action of a potent tricyclic cholinesterase inhibitor ethopropazine on the hydrolysis of acetylthiocholine and butyrylthiocholine by purified horse serum butyrylcholinesterase (EC 3.1.1.8) was investigated at 25 and 37 degrees C. The enzyme activities were measured on a stopped-flow apparatus and the analysis of experimental data was done by applying a six-parameter model for substrate hydrolysis. The model, which was introduced to explain the kinetics of Drosophila melanogaster acetylcholinesterase [Stojan et al. (1998) FEBS Lett. 440, 85-88], is defined with two dissociation constants and four rate constants and can describe both cooperative phenomena, apparent activation at low substrate concentrations and substrate inhibition by excess of substrate. For the analysis of the data in the presence of ethopropazine at two temperatures, we have enlarged the reaction scheme to allow primarily its competition with the substrate at the peripheral site, but the competition at the acylation site was not excluded. The proposed reaction scheme revealed, upon analysis, competitive effects of ethopropazine at both sites; at 25 degrees C, three enzyme-inhibitor dissociation constants could be evaluated; at 37 degrees C, only two constants could be evaluated. Although the model considers both cooperative phenomena, it appears that decreased enzyme sensitivity at higher temperature, predominantly for the ligands at the peripheral binding site, makes the determination of some expected enzyme substrate and/or inhibitor complexes technically impossible. The same reason might also account for one of the paradoxes in cholinesterases: activities at 25 degrees C at low substrate concentrations are higher than at 37 degrees C. Positioning of ethopropazine in the active-site gorge by molecular dynamics simulations shows that A328, W82, D70, and Y332 amino acid residues stabilize binding of the inhibitor.

Animals↗
PubMed1998

The Src-like tyrosine kinase Hck is activated by granulocyte colony-stimulating factor (G-CSF) and docks to the activated G-CSF receptor.

Activation of the granulocyte colony-stimulating factor receptor (G-CSF-R) leads to tyrosine-phosphorylation of multiple cytoplasmic components. To date, the kinases Jak1, Jak2, Tyk2, Lyn, and Syk have been implicated in this process. However, it is unknown if other kinases might be involved in the diverse responses from the G-CSF-R, which include mitogenesis, survival, differentiation, and functional activation of responsive cells. The hematopoietic cell kinase (Hck) is a member of the Src-family of kinases known to be expressed in cells of the granulocytic lineage. It also interacts with the gp130 subunit of the LIF/IL-6 receptors, which is closely related to the G-CSF-R, and so represents a good candidate for mediating at least some of the downstream signaling from the G-CSF-R. Therefore, we investigated the activation of Hck by the G-CSF-R in intact cells as well as in vitro. These studies revealed recruitment of Hck to activated G-CSF-R, mediated by direct binding via its SH2 domain to multiple phosphotyrosines of the receptor. In addition, we show that Hck becomes activated upon G-CSF treatment and is, in turn, able to phosphorylate the G-CSF-R, indicating a clear functional and physical involvement in G-CSF signaling.

Animals↗
PubMed2001

Thy-1 associated pp85--90 is a potential docking site for SH2 domain-containing signal transduction molecules.

Thy-1, a glycosylphosphatidylinositol (GPI)-anchored glycoprotein expressed at high levels on thymocytes, has been implicated in positive and negative signal transduction. We show that Thy-1 associates with a protein of 85--90 kDa, which is prominently phosphorylated in vitro as well as in vivo following the stimulation of thymocytes with pervanadate. pp85--90 is not identical to known proteins that are phosphorylated following T cell activation. The SH2 domains of fyn, csk, phosphatidylinositol 3'-kinase, rasGAP, vav and lck bind to pp85--90 with varying affinities. The SH2 domains of ZAP70, SHP-1 and PLC gamma 1 and the SH3 domains of lck, vav and HS1 did not bind to pp85--90. The molecular weight, iso-electric point, efficient phosphorylation by fyn and lck and preferential binding to the SH2 domain of fyn compared to that of lck indicate that Thy-1-associated pp85-90 may be identical to a recently cloned, fyn-associated transmembrane adaptor protein, PAG-85.

Animals↗
PubMed1994

Combined conformational search and finite-difference Poisson-Boltzmann approach for flexible docking. Application to an operator mutation in the lambda repressor-operator complex.

The N-terminal domain of the phage lambda repressor binds as a dimer to its palindromic DNA operator sequence. In addition to a helix-turn-helix DNA recognition motif, the first six amino acids of the phage lambda repressor form a flexible peptide segment which wraps around DNA. Site-directed mutagenesis studies have shown that amino acid replacements or partial removal of the arm structure, or changes in the DNA sequence contacting the N-terminal arm, can lower the repressor-operator binding affinity by several orders of magnitude. The finite-difference Poisson-Boltzmann approach in combination with a conformational search procedure was used to study energetic contributions of the lambda arm to repressor-operator recognition based on the high resolution X-ray structure. It allows for the local relaxation of the structure upon changing the DNA sequence in the lambda arm binding region. A simplified potential energy function including torsional, truncated Lennard-Jones and approximate electrostatic terms is used in the initial step to screen out energetically unfavorable structures. The electrostatic energy of selected conformations is subsequently calculated more accurately using the finite-difference Poisson-Boltzmann approach. The method was applied to study the effect of a C-->T mutation at position 6 of the consensus half-site of the operator. This base-pair contacts Lys4 which is part of the arm segment. Keeping only the Lys4 side-chain mobile and with the wild-type DNA operator sequence, several conformations close to the X-ray structure were identified as those with lowest energy. In the case of the DNA mutation, lowest energy conformations differed significantly from those selected for the wild-type sequence. These initial calculations indicate that the approach might be a useful tool to estimate conformational and energetic effects upon mutagenesis of protein-DNA complexes.

Base Sequence↗
PubMed1996

Gene therapy for cancer--in the dock, blown off course or full speed ahead?

Gene therapy no longer seems to generate the unlimited optimism that it once inspired. So much so that the field has recently attracted the close scrutinies of the Director of the NIH himself. In this introductory chapter, the background is presented to the rise, and apparent decline, of the gene therapy of cancer and serves as a prelude to this issue of Cancer Metastasis Reviews which is designed to ask whether the field is worthy of its highly-priced and highly-hyped market profile.

Forecasting↗
PubMed2005

Lipid membrane-induced optimization for ligand-receptor docking: recent tools and insights for the "membrane catalysis" model.

Cells in living organisms are regulated by chemical and physical stimuli from their environment. Often, ligands interact with membrane receptors to trigger responses and Sargent and Schwyzer conceived a model to describe this process, "membrane catalysis". There is a notion that the physical organization of membranes can control the response of cells by speeding up reactions. We revisit the "membrane catalysis" model in the light of recent technical, methodological and theoretical advances and how they can be exploited to highlight the details of membrane mediated ligand-receptor interactions. We examine the possible effects that ligand concentration causes in the membrane catalysis and focus our attention in techniques used to determine the partition constant. The hypothetical diffusional advantage associated with membrane catalysis is discussed and the applicability of existing models is assessed. The role of in-depth location and orientation of ligands is explored emphasizing the contribution of new analysis methods and spectroscopic techniques. Results suggest that membranes can optimize the interaction between ligands and receptors through several different effects but the relative contribution of each must be carefully investigated. We certainly hope that the conjugation of the methodological and technical advances here reported will revive the interest in the membrane catalysis model.

Biomimetic Materials↗
PubMed2002

Initial radiographic findings of early gastric cancer detected in health check programs and human "dry dock" (multiphasic screening) collective health checks and treated by endoscopic mucosal resection.

BACKGROUND: The purpose of this study was to evaluate the capacity of detection (detectability), by radiographic examination, of minute gastric cancer that was indicated for endoscopic mucosal resection (EMR). METHODS: Fifty-five lesions in 55 patients with minute gastric cancer were endoscopically resected between 1992 and 2000 at the Foundation for Detection of Early Gastric Carcinoma. Of these 55 patients, 33 patients underwent indirect (with image intensifier and 100-mm roll film) and/or direct radiographic examination of the upper gastrointestinal tract as the initial screening examination, and subsequent upper gastrointestinal endoscopy. The remaining 22 patients underwent upper gastrointestinal endoscopy as the initial screening examination. As the first step, radiographic (indirect and direct) images were reviewed, and the abnormalities which had eventually led to the detection of the minute early gastric cancer (EGC) were reconfirmed. Then, they were analyzed in terms of the reproducibility of abnormal findings which enabled the detection of such a minute EGC, and in terms of whether they could be treated by EMR. The size, morphology, and location of the radiographically detected lesions were analyzed. RESULTS: Seventeen lesions of EGC were detected in the group in which indirect radiography was initially performed. Of these 17 lesions, some abnormality corresponding to the site of the lesion was pointed out in 7 lesions (2 lesions of type IIa and 5 lesions of type IIc). On the other hand, the remaining 10 lesions (type IIa, 3; type IIc, 5; type IIa + IIc, 1; and type IIb, 1) were detected by endoscopy, which was carried out to confirm the other abnormalities in the indirect radiographic images. Sixteen lesions of EGC were detected in the group in which direct radiography was initially performed. Of these 16 lesions, some abnormality corresponding to the site of the lesion was pointed out in 8 lesions (4 lesions of type IIa and 4 lesions of type IIc). The remaining 8 lesions (3 lesions of type IIa and 5 lesions of type IIc) were not detected by direct radiography. CONCLUSION: Indirect and direct radiographic examination enabled the detection of approximately 50% of EGCs which could be treated by endoscopic resection. The significance of radiographic examination should not be underestimated, even in the detection of EGCs which can be endoscopically resected.

Gastric Mucosa↗
PubMed2005

Human topoisomerase I poisoning: docking protoberberines into a structure-based binding site model.

Using the X-ray crystal structure of the human topoisomerase I (top1) - DNA cleavable complex and the Sybyl software package, we have developed a general model for the ternary cleavable complex formed with four protoberberine alkaloids differing in the substitution on the terminal phenyl rings and covering a broad range of the top1-poisoning activities. This model has the drug intercalated with its planar chromophore between the -1 and +1 base pairs flanking the cleavage site, with the nonplanar portion pointing into the minor groove. The ternary complexes were geometry-optimized and relative interaction energies, computed by using the Tripos force field, were found to rank in correct order the biological potency of the compounds; in addition, the model is also consistent with the top1-poisoning inactivity of berberine, a major prototype of the protoberberine alkaloids. The model might serve as a rational basis for elaboration of the most active compound as a lead structure, in order to develop more potent top1 poisons as next generation anti-cancer drugs.

Berberine Alkaloids↗