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PubMed2005

The role of docking interactions in mediating signaling input, output, and discrimination in the yeast MAPK network.

Cells use a network of mitogen-activated protein kinases (MAPKs) to coordinate responses to diverse extracellular signals. Here, we examine the role of docking interactions in determining connectivity of the yeast MAPKs Fus3 and Kss1. These closely related kinases are activated by the common upstream MAPK kinase Ste7 yet generate distinct output responses, mating and filamentous growth, respectively. We find that docking interactions are necessary for communication with the kinases and that they can encode subtle differences in pathway-specific input and output. The cell cycle arrest mediator Far1, a mating-specific substrate, has a docking motif that selectively binds Fus3. In contrast, the shared partner Ste7 has a promiscuous motif that binds both Fus3 and Kss1. Structural analysis reveals that Fus3 interacts with specific and promiscuous peptides in conformationally distinct modes. Induced fit recognition may allow docking peptides to achieve discrimination by exploiting subtle differences in kinase flexibility.

Amino Acid Sequence↗
PubMed1996

Electrostatic properties of cytochrome f: implications for docking with plastocyanin.

The electrostatic properties of cytochrome f (cyt f), a member of the cytochrome b6f complex and reaction partner with plastocyanin (PC) in photosynthetic electron transport, are qualitatively studied with the goal of determining the mechanism of electron transfer between cyt f and PC. A crystal structure for cyt f was analyzed with the software package GRASP, revealing a large region of positive potential generated by a patch of positively charged residues (including K58, K65, K66, K122, K185, K187, and R209) and reinforced by the iron center of the heme. This positive field attracts the negative charges of the two acidic patches on the mobile electron carrier PC. Three docked complexes are obtained for the two proteins, based on electrostatic or hydrophobic interactions or both and on steric fits by manual docking methods. The first of these three complexes shows strong electrostatic interactions between K187 on cyt f and D44 on PC and between E59 on PC and K58 on cyt f. Two other manually docked complexes are proposed, implicating H87 on PC as the electron-accepting site from the iron center of cyt f through Y1. The second complex maintains the D44/K187 cross-link (but not the E59/K58 link) while increasing hydrophobic interactions between PC and cyt f. Hydrophobic interactions are increased still further in the third complex, whereas the link between K187 on cyt f and D44 on PC is broken. The proposed reaction mechanism, therefore, involves an initial electrostatic docking complex that gives rise to a nonpolar attraction between the regions surrounding H87 on PC and Y1 on cyt f, providing for an electron-transfer active complex.

Binding Sites↗
PubMed1989

Leptospiral and hepatitis A antibodies amongst windsurfers and waterskiers in Bristol City Docks.

Previous epidemiological studies have detected a substantial risk of gastroenteritis associated with snorkel swimming events in the Bristol City Docks. The event has since been discontinued. Similar risks were not identified at that time for surface-based events. A subsequent fatality from Weil's disease (Leptospirosis) and a case of Hepatitis A associated with surface water immersion in the Bristol City Docks water prompted this study of Leptospiral and Hepatitis A immunity amongst regular windsurfers and waterskiers. Although one person showed evidence of past Leptospiral infection and several people showed evidence of previous Hepatitis A, a causal association with Docks water exposure was not established. Nevertheless, there was sufficient public concern to justify the introduction of precautions against the potential health risks associated with immersion in the City Docks. The study findings and these preventive measures are described.

Adolescent↗
PubMed2000

Trio combines with dock to regulate Pak activity during photoreceptor axon pathfinding in Drosophila.

Correct pathfinding by Drosophila photoreceptor axons requires recruitment of p21-activated kinase (Pak) to the membrane by the SH2-SH3 adaptor Dock. Here, we identify the guanine nucleotide exchange factor (GEF) Trio as another essential component in photoreceptor axon guidance. Regulated exchange activity of one of the two Trio GEF domains is critical for accurate pathfinding. This GEF domain activates Rac, which in turn activates Pak. Mutations in trio result in projection defects similar to those observed in both Pak and dock mutants, and trio interacts genetically with Rac, Pak, and dock. These data define a signaling pathway from Trio to Rac to Pak that links guidance receptors to the growth cone cytoskeleton. We propose that distinct signals transduced via Trio and Dock act combinatorially to activate Pak in spatially restricted domains within the growth cone, thereby controlling the direction of axon extension.

Adaptor Proteins, Signal Transducing↗
PubMedDate not supplied

Docking interactions in the mitogen-activated protein kinase cascades.

Regulation of cellular functions and responses utilizes a number of the signal transduction pathways. Each pathway should transduce signals with high efficiency and fidelity to avoid unnecessary crosstalks. The mitogen-activated protein kinase (MAPK) cascades regulate a wide variety of cellular functions, including cell proliferation, differentiation, and stress responses. MAPK is activated by MAPK kinase; phosphorylates various targets, including transcription factors and MAPK-activated protein kinases; and is inactivated by several phosphatases. Recent studies have provided a cue to understand the molecular mechanism underlying the signal transduction through the MAPK cascades. In the MAPK cascades, docking interactions, which are achieved through a site outside the catalytic domain of MAPKs, regulate the efficiency and specificity of the enzymatic reactions. The docking interaction is different from a transient enzyme-substrate interaction through the active center. It has been shown that activators, substrates, and inactivators of MAPKs utilize a common site on MAPKs in the docking interaction. Then, the docking interaction may regulate not only the efficiency and specificity of the cascades, but also the ordered and integrated signaling.

Animals↗
PubMed2003

Humanized docking system for assembly of targeting drug delivery complexes.

Targeted drug delivery requires 'loading' drugs onto targeting proteins. Traditional technologies for loading drugs rely on chemical conjugation of drugs or drug carriers to targeting proteins. An alternative approach might rely on assembly of targeting complexes using a docking system that includes two components: a 'docking' tag fused to a targeting protein, and a 'payload' module containing an adapter protein for non-covalent binding to the docking tag. We describe here a fully humanized adapter/docking tag system based on non-covalent interaction between two fragments of human pancreatic RNase I. A 15 amino acid long N-terminal fragment of RNase I designed to serve as a docking tag, was fused to the N-terminus of human vascular endothelial growth factor that served as a targeting protein. An 18-125 and an 18-127 amino acid long fragments of RNase I were engineered, expressed and refolded into active conformations to serve as adapter proteins. Interactions between the targeting and adapter proteins were characterized using enzymatic analysis and surface plasmon resonance. Targeting DNA delivery complexes were assembled, characterized by dynamic light scattering, and found to be very effective in receptor-mediated DNA delivery.

Cell Line↗
PubMed2001

Synthesis and receptor docking studies of N-substituted indole-2-carboxylic acid esters as a search for COX-2 selective enzyme inhibitors.

A series of N-substituted indole-2-carboxylic acid esters have been prepared by replacing the benzoyl group of indomethacin with a benzyl and a phenyl group. The carbocyclic acid side chain was extended via creating an ester structure by using several dialkylaminoalkyl groups. The receptor docking studies were performed to investigate the docking mode of each compound by using DOCK 4.0. All the compounds were shown to be docked at the site where intact flurbiprofen was embedded for COX-1 and s-58 (1-phenylsulphonamide-3-trifluoromethyl-5-para-bromophenylpyrazole) for COX-2. It was predicted that N-phenyl-indole-2-carboxylic acid piperazine ester 22 can be a fairly strong COX-2 selective compound which was compared to the others. Other predicted COX-2 selective compounds included are N--H indole-2-carboxylic acid diethyl 30 and piperazine 34 esters. In view of these findings, compounds 22, 30 and 34 were chosen for the in vitro biological assays.

Animals↗
PubMed2003

Flexible ligand docking using evolutionary algorithms: investigating the effects of variation operators and local search hybrids.

The docking of ligands to proteins can be formulated as a computational problem where the task is to find the most favorable energetic conformation among the large space of possible protein-ligand complexes. Stochastic search methods such as evolutionary algorithms (EAs) can be used to sample large search spaces effectively and is one of the commonly used methods for flexible ligand docking. During the last decade, several EAs using different variation operators have been introduced, such as the ones provided with the AutoDock program. In this paper we evaluate the performance of different EA settings such as choice of variation operators, population size, and usage of local search. The comparison is performed on a suite of six docking problems previously used to evaluate the performance of search algorithms provided with the AutoDock program package. The results from our investigation confirm that the choice of variation operators has an impact on the search-capabilities of EAs. The introduced DockEA using the best settings found obtained the overall best docking solutions compared to the Lamarckian GA (LGA) provided with AutoDock. Furthermore, the DockEA proved to be more robust than the LGA (in terms of reproducing the results in several runs) on the more difficult problems with a high number of flexible torsion angles.

Algorithms↗
PubMed1999

A MAP kinase docking site is required for phosphorylation and activation of p90(rsk)/MAPKAP kinase-1.

Activation of the various mitogen-activated protein (MAP) kinase pathways converts many different extracellular stimuli into specific cellular responses by inducing the phosphorylation of particular groups of substrates. One important determinant for substrate specificity is likely to be the amino-acid sequence surrounding the phosphorylation site; however, these sites overlap significantly between different MAP kinase family members. The idea is now emerging that specific docking sites for protein kinases are involved in the efficient binding and phosphorylation of some substrates [1] [2] [3] [4]. The MAP kinase-activated protein (MAPKAP) kinase p90 rsk contains two kinase domains [5]: the amino-terminal domain (D1) is required for the phosphorylation of exogenous substrates whereas the carboxy-terminal domain (D2) is involved in autophosphorylation. Association between the extracellular signal-regulated kinase (Erk) MAP kinases and p90(rsk) family members has been detected in various cell types including Xenopus oocytes [6] [7] [8], where inactive p90(rsk) is bound to the inactive form of the Erk2- like MAP kinase p42(mpk1). Here, we identify a new MAP kinase docking site located at the carboxyl terminus of p90(rsk). This docking site was required for the efficient phosphorylation and activation of p90(rsk) in vitro and in vivo and was also both necessary and sufficient for the stable and specific association with p42(mpk1). The sequence of the docking site was conserved in other MAPKAP kinases, suggesting that it might represent a new class of interaction motif that facilitates efficient and specific signal transduction by MAP kinases.

Amino Acid Sequence↗
PubMed2000

A method for including protein flexibility in protein-ligand docking: improving tools for database mining and virtual screening.

Second-generation methods for docking ligands into their biological receptors, such as FLOG, provide for flexibility of the ligand but not of the receptor. Molecular dynamics based methods, such as free energy perturbation, account for flexibility, solvent effects, etc., but are very time consuming. We combined the use of statistical analysis of conformational samples from short-run protein molecular dynamics with grid-based docking protocols and demonstrated improved performance in two test cases. Our statistical analysis explores the importance of the average strength of a potential interaction with the biological target and optionally applies a weighting depending on the variability in the strength of the interaction seen during dynamics simulation. Using these methods, we improved the num-top-ranked 10% of a database of drug-like molecules, in searches based on the three-dimensional structure of the protein. These methods are able to match the ability of manual docking to assess likely inactivity on steric grounds and indeed to rank order ligands from a homologous series of cyclooxygenase-2 inhibitors with good correlation to their true activity. Furthermore, these methods reduce the need for human intervention in setting up molecular docking experiments.

Combinatorial Chemistry Techniques↗
PubMed2002

Crystal structures of MAP kinase p38 complexed to the docking sites on its nuclear substrate MEF2A and activator MKK3b.

The structures of the MAP kinase p38 in complex with docking site peptides containing a phi(A)-X-phi(B) motif, derived from substrate MEF2A and activating enzyme MKK3b, have been solved. The peptides bind to the same site in the C-terminal domain of the kinase, which is both outside the active site and distinct from the "CD" domain previously implicated in docking site interactions. Mutational analysis on the interaction of p38 with the docking sites supports the crystallographic models and has uncovered two novel residues on the docking groove that are critical for binding. The two peptides induce similar large conformational changes local to the peptide binding groove. The peptides also induce unexpected and different conformational changes in the active site, as well as structural disorder in the phosphorylation lip.

Adenosine Triphosphate↗
PubMed1996

A docking and modelling strategy for peptide-RNA complexes: applications to BIV Tat-TAR and HIV Rev-RBE.

BACKGROUND: In spite of the great interest in the interaction between RNAs and proteins, no general protocol for modelling these complexes is presently available. This methodological vacuum is particularly acute because the structure of few such complexes is known. RESULTS: A general strategy for docking and modelling RNA-protein complexes has been developed. The docking procedure involves minimizing electrostatic and van der Waals' interaction energies of conformationally rigid structures during docking. After docking, libraries of amino acid sidechain conformations are searched to obtain the best interactions between the peptide and the RNA. Using this method, we have reproduced the structure of a bovine immunodeficiency virus (BIV) Tat peptide bound to BIV TAR RNA and have developed a model for the structure of the arginine-rich HIV-1 Rev peptide (Rev34-50) interacting with the Rev-binding element (RBE). CONCLUSIONS: The resulting model of the Rev34-50-RBE complex predicts that although no single arginine sidechain is responsible for complex formation, residues Arg2, Arg5 and Arg11 are more important for binding than the other arginine residues in the peptide. One model is supported by binding measurements performed on wild-type and mutant RBE molecules with the peptide.

Animals↗
PubMed1994

Fluorescence-detected stopped flow with a pyrene labeled substrate reveals that guanosine facilitates docking of the 5' cleavage site into a high free energy binding mode in the Tetrahymena ribozyme.

Fluorescence-detected stopped flow kinetics are reported for binding of pyrene (pyr) labeled oligonucleotide substrates, pyrCUCUA and pyrCCUCUA, to the L-21 ScaI ribozyme from Tetrahymena thermophila. Both oligomer substrates contain a UA sequence that mimics the cleavage site where pG attacks the self-splicing group I intron from which the ribozyme was derived. Kinetics were measured in the presence and absence of saturating 5'-monophosphate guanosine substrate (pG) at 5 mM Mg2+ and 15 degrees C. In the absence of pG, binding of both oligonucleotide substrates is consistent with a one step mechanism involving only base pairing. Upon addition of pG, pyrCCUCUA is observed to bind in two steps: base pairing to the ribozyme to form the P1 helix and, presumably, subsequent docking of the P1 helix into the catalytic core. A third transient is also observed, which likely includes the chemical step following docking. All rate constants are measured for this mechanism. Surprisingly, the equilibrium constant for docking, K2, is unfavorable in the absence of pG (K2 < 1) and only modestly favorable in the presence of pG (K2 = 4). These results contrast with those for a 5' exon mimic, pyrCCUCU, in which docking is strongly favored under the above conditions in the absence of pG; K2 = 100 [Bevilacqua, P. C., Kierzek, R., Johnson, K. A., & Turner, D. H. (1992) Science 258, 1355-1358]. These results suggest an unfavorable interaction between the ribozyme and the pA at the site of cleavage. Implications are discussed for the catalytic strategy of the ribozyme and for the self-splicing cascade that occurs in nature.

Animals↗
PubMed1993

Tertiary interactions with the internal guide sequence mediate docking of the P1 helix into the catalytic core of the Tetrahymena ribozyme.

The L-21 ScaI ribozyme catalyzes sequence-specific cleavage of an oligonucleotide substrate. Cleavage is preceded by base pairing of the substrate to the internal guide sequence (IGS) at the 5' end of the ribozyme to form a short RNA duplex (P1). Tertiary interactions between P1 and the catalytic core dock P1 into the active site of the ribozyme. These include interactions between the catalytic core and 2'-hydroxyls of the substrate at nucleotide positions -3u and perhaps -2c. In this study, 2'-hydroxyls of the IGS strand that contribute to P1 recognition by the ribozyme are identified. IGS 2'-hydroxyls (nucleotide positions 22-27) were individually modified to either 2'-deoxy or 2'-methoxynucleotides within full-length semisynthetic L-21 ScaI ribozymes generated using T4 DNA ligase. Thermodynamic and kinetic characterization of the resulting IGS variant ribozymes justify the following conclusions: (i) 2'-Hydroxyls at nucleotide positions G22 and G25 play a critical energetic role in docking P1 into the catalytic core, contributing 2.6 and 2.1 kcal.mol-1, respectively. (ii) The loss of binding energy is manifest primarily as an increase in the rate of dissociation. Because turnover for the wild-type ribozyme is limited by product dissociation, G22 and G25 deoxy variants display up to a 20-fold increase in the multiple-turnover rate at saturating substrate. (iii) IGS tertiary interactions are energetically coupled with the tertiary interactions made to the substrate, consistent with P1 becoming undocked from its binding site in J8/7 upon substitution of either the G22 or G25 2'-hydroxyl. (iv) The G22 deoxy variant loses energetic coupling between guanosine and substrate binding, suggesting that in this variant the P1 helix is also undocked from its binding site in J4/5, the proposed site of guanosine and substrate interaction. Therefore, in combinations with previous studies four P1 2'-hydroxyls are implicated as important for docking. The contributions of the 2'-hydroxyl tertiary interactions are not equivalent and follow the hierarchical order G22 > G25 >> -3u > -2c. Because the G22 2'-hydroxyl appears to mediate P1 docking into both J8/7 and J4/5, it may serve as the molecular linchpin for the recognition of P1 by the catalytic core.

Animals↗
PubMed2002

Dynamic docking of myosin and actin observed with resonance energy transfer.

Atomic models of myosin subfragment-1 (S1) and the actin filament are docked together using resonance energy-transfer data from both pre- and postpowerstroke conditions. The quality of the resulting best fits discriminated between neck-region orientations of the S1 for a given set of experimental conditions. For measurements of the postpowerstroke states in the presence of ADP, resonance energy-transfer data alone are sufficient to dock the atomic models and provide evidence that S1 exists with at least two neck-region orientations under these conditions. To dock the prepowerstroke state, resonance energy-transfer data were used in combination with previous chemical cross-linking data to determine that a neck-region orientation similar to that of a proposed prepowerstroke state best fit the data. The resulting models determined independently from electron microscopy compare favorably with micrographs from the recent literature. The docking models by resonance energy transfer suggest that the larger movements in the light-chain binding domain are accompanied by twisting and rotating movements of the catalytic domain, causing a tilt of approximately 30 degrees during the weak-to-strong transition. This transition provides the displacement necessary to support motility and force generation.

Actins↗
PubMed2003

Membrane-docking loops of the cPLA2 C2 domain: detailed structural analysis of the protein-membrane interface via site-directed spin-labeling.

C2 domains are protein modules found in numerous eukaryotic signaling proteins, where their function is to target the protein to cell membranes in response to a Ca(2+) signal. Currently, the structure of the interface formed between the protein and the phospholipid bilayer is inaccessible to high-resolution structure determination, but EPR site-directed spin-labeling can provide a detailed medium-resolution view of this interface. To apply this approach to the C2 domain of cytosolic phospholipase A(2) (cPLA(2)), single cysteines were introduced at all 27 positions in the three Ca(2+)-binding loops and labeled with a methanethiosulfonate spin-label. Altogether, 24 of the 27 spin-labeled domains retained Ca(2+)-activated phospholipid binding. EPR spectra of these 24 labeled domains obtained in the presence and absence of Ca(2+) indicate that Ca(2+) binding triggers subtle changes in the dynamics of two localized regions within the Ca(2+)-binding loops: one face of the loop 1 helix and the junction between loops 1 and 2. However, no significant changes in loop structure were detected upon Ca(2+) binding, nor upon Ca(2+)-triggered docking to membranes. EPR depth parameters measured in the membrane-docked state allow determination of the penetration depth of each residue with respect to the membrane surface. Analysis of these depth parameters, using an improved, generalizable geometric approach, provides the most accurate picture of penetration depth and angular orientation currently available for a membrane-docked peripheral protein. Finally, the observation that Ca(2+) binding does not trigger large rearrangements of the membrane-docking loops favors the electrostatic switch model for Ca(2+) activation and disfavors, or places strong constraints on, the conformational switch model.

Amino Acid Substitution↗
PubMed2006

Comparison of the binding and reactivity of plant and mammalian peroxidases to indole derivatives by computational docking.

The oxidation of melatonin by the mammalian myeloperoxidase (MPO) provides protection against the damaging effects of reactive oxygen species. Indole derivatives, such as melatonin and serotonin, are also substrates of the plant horseradish peroxidase (HRP), but this enzyme exhibits remarkable differences from MPO in the specificity and reaction rates for these compounds. A structural understanding of the determinants of the reactivity of these enzymes to indole derivatives would greatly aid their exploitation for biosynthetic and drug design applications. Consequently, after validation of the docking procedure, we performed computational docking of melatonin and serotonin to structural models of the ferric and compound I and II (co I and co II, respectively) states of HRP and MPO. The substrates dock at the heme edge on the distal side, but with different orientations in the two proteins. The distal cavity is larger in MPO than in HRP; however, in MPO, the substrates make closer contacts with the heme involving ring stacking, whereas in HRP, no ring stacking is observed. The observed differences in substrate binding may contribute to the higher reaction rates and lower substrate specificity of MPO relative to those of HRP. The docking results, along with the previously measured heme-protein reduction potentials, suggest that the differentially lowered reaction rates of co II of HRP and MPO with respect to those of co I could stem from as yet undetermined conformational or electrostatic differences between the co I and co II states of MPO, which are absent in HRP.

Animals↗
PubMed2000

Heteronuclear NMR and soft docking: an experimental approach for a structural model of the cytochrome c553-ferredoxin complex.

The combination of docking algorithms with NMR data has been developed extensively for the studies of protein-ligand interactions. However, to extend this development for the studies of protein-protein interactions, the intermolecular NOE constraints, which are needed, are more difficult to access. In the present work, we describe a new approach that combines an ab initio docking calculation and the mapping of an interaction site using chemical shift variation analysis. The cytochrome c553-ferredoxin complex is used as a model of numerous electron-transfer complexes. The 15N-labeling of both molecules has been obtained, and the mapping of the interacting site on each partner, respectively, has been done using HSQC experiments. 1H and 15N chemical shift analysis defines the area of both molecules involved in the recognition interface. Models of the complex were generated by an ab initio docking software, the BiGGER program (bimolecular complex generation with global evaluation and ranking). This program generates a population of protein-protein docked geometries ranked by a scoring function, combining relevant stabilization parameters such as geometric complementarity surfaces, electrostatic interactions, desolvation energy, and pairwise affinities of amino acid side chains. We have implemented a new module that includes experimental input (here, NMR mapping of the interacting site) as a filter to select the accurate models. Final structures were energy minimized using the X-PLOR software and then analyzed. The best solution has an interface area (1037.4 A2) falling close to the range of generally observed recognition interfaces, with a distance of 10.0 A between the redox centers.

Amino Acid Sequence↗