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PubMed2007

Src docks to A-kinase anchoring protein gravin, regulating beta2-adrenergic receptor resensitization and recycling.

Gravin (AKAP12) is a membrane-associated scaffold that provides docking for protein kinases, phosphatases, and adaptor molecules obligate for resensitization and recycling of beta(2)-adrenergic receptors. Gravin binds to the cell membrane in a Ca(2+)-sensitive manner and to receptors through well characterized protein-protein interactions. Although the interaction of serine/threonine, cyclic AMP-dependent protein kinase with protein kinase A-anchoring proteins is well described and involves a kinase regulatory subunit binding domain in the C terminus of these proteins, far less is known about tyrosine kinase docking to members of this family of scaffolds. The non-receptor tyrosine kinase Src regulates resensitization of beta(2)-adrenergic receptors and docks to gravin. Gravin displays nine proline-rich domains distributed throughout the molecule. One class I ligand for Src homology domain 3 docking, found in the N terminus ((10)RXPXXP(15)) of gravin, is shown to bind Src. Binding of Src to gravin activates the intrinsic tyrosine kinase of Src. Mutagenesis/deletion of the class I ligand (P15A,P16A) on the N terminus of gravin abolishes both the docking of Src to gravin as well as the receptor resensitization and recycling catalyzed by gravin. The Src-binding peptide-(1-51) of gravin behaves as a dominant-negative for AKAP gravin regulation of receptor resensitization/recycling. The tyrosine kinase Src plays an essential role in the AKAP gravin-mediated receptor resensitization and recycling, an essential aspect of receptor biology.

A Kinase Anchor Proteins↗

PubMed2005

Granuphilin molecularly docks insulin granules to the fusion machinery.

The Rab27a effector granuphilin is specifically localized on insulin granules and is involved in their exocytosis. Here we show that the number of insulin granules morphologically docked to the plasma membrane is markedly reduced in granuphilin-deficient beta cells. Surprisingly, despite the docking defect, the exocytosis of insulin granules in response to a physiological glucose stimulus is significantly augmented, which results in increased glucose tolerance in granuphilin-null mice. The enhanced secretion in mutant beta cells is correlated with a decrease in the formation of the fusion-incompetent syntaxin-1a-Munc18-1 complex, with which granuphilin normally interacts. Furthermore, in contrast to wild-type granuphilin, its mutant that is defective in binding to syntaxin-1a fails to restore granule docking or the protein level of syntaxin-1a in granuphilin-null beta cells. Thus, granuphilin not only is essential for the docking of insulin granules but simultaneously imposes a fusion constraint on them through an interaction with the syntaxin-1a fusion machinery. These findings provide a novel paradigm for the docking machinery in regulated exocytosis.

Adenoviridae↗

PubMed1999

Docking of hydrophobic ligands with interaction-based matching algorithms.

MOTIVATION: Matching of chemical interacting groups is a common concept for docking and fragment placement algorithms in computer-aided drug design. These algorithms have been proven to be reliable and fast if at least a certain number of hydrogen bonds or salt bridges occur. However, the algorithms typically run into problems if hydrophobic fragments or ligands should be placed. In order to dock hydrophobic fragments without significant loss of computational efficiency, we have extended the interaction model and placement algorithms in our docking tool FlexX. The concept of multi-level interactions is introduced into the algorithms for automatic selection and placement of base fragments. RESULTS: With the multi-level interaction model and the corresponding algorithmic extensions, we were able to improve the overall performance of FlexX significantly. We tested the approach with a set of 200 protein-ligand complexes taken from the Brookhaven Protein Data Bank (PDB). The number of test cases which can be docked within 1.5 A RMSD from the crystal structure can be increased from 58 to 64%. The performance gain is paid for by an increase in computation time from 73 to 91 s on average per protein-ligand complex. AVAILABILITY: The FlexX molecular docking software is available for UNIX platforms IRIX, Solaris and Linux. See http://cartan.gmd.de/FlexX for additional information.

Algorithms↗

PubMed2006

Solvated docking: introducing water into the modelling of biomolecular complexes.

MOTIVATION: Interfacial water, which plays an important role in mediating biomolecular interactions, has been neglected in the modelling of biomolecular complexes. METHODS: We present a solvated docking approach that explicitly accounts for the presence of water in protein-protein complexes. Our solvated docking protocol is based on the concept of the first encounter complex in which a water layer is present in-between the molecules. It mimics the pathway from this initial complex towards the final assembly in which most waters have been expelled from the interface. Docking is performed from solvated biomolecules and waters are removed in a biased Monte Carlo procedure based on water-mediated contact propensities obtained from an analysis of high-resolution crystal structures. RESULTS: We demonstrate the feasibility of this approach for protein-protein complexes representing both 'wet' and 'dry' interfaces. Solvated docking leads to improvements both in quality and scoring. Water molecules are recovered that closely match the ones in the crystal structures. AVAILABILTY: Solvated docking will be made available in the future release of HADDOCK version 2.0 (http://www.nmr.chem.uu.nl/haddock).

Binding Sites↗

PubMed2001

Rsk2 allosterically activates estrogen receptor alpha by docking to the hormone-binding domain.

We describe a novel mechanism for transcriptional regulation, in which docking of p90 ribosomal S6 kinase 2 (Rsk2) to the hormone-binding domain (HBD) of estrogen receptor alpha (ERalpha) induces a conformational change that enhances the transcriptional activation function contained in the HBD. A constitutively active mutant of Rsk2 specifically enhances ERalpha-mediated transcription by phosphorylation of Ser167 in ERalpha and by physically associating with residues 326-394 of the ERalpha HBD. The anti-estrogen 4-hydroxytamoxifen blocks Rsk2-mediated activation of ERalpha, by inducing a conformation of ERalpha in which the Rsk2 docking site is masked. Transcriptional activation and docking are specific for ERalpha and do not occur with the related isoform, ERbeta. ERalpha phosphorylation, docking and transcriptional activation are regulated by the Rsk2 N-terminal kinase domain. The allosteric regulation of a target protein, independent of phosphorylation, may be paradigmatic of a general function for protein kinase docking sites.

Allosteric Regulation↗

PubMed2003

A docking site determining specificity of Pbs2 MAPKK for Ssk2/Ssk22 MAPKKKs in the yeast HOG pathway.

Mitogen-activated protein kinase (MAPK) cascades are conserved signaling modules composed of three sequentially activated kinases (MAPKKK, MAPKK and MAPK). Because individual cells contain multiple MAPK cascades, mechanisms are required to ensure the fidelity of signal transmission. In yeast, external high osmolarity activates the HOG (high osmolarity glycerol) MAPK pathway, which consists of two upstream branches (SHO1 and SLN1) and common downstream elements including the Pbs2 MAPKK and the Hog1 MAPK. The Ssk2/Ssk22 MAPKKKs in the SLN1 branch, when activated, exclusively phosphorylate the Pbs2 MAPKK. We found that this was due to an Ssk2/Ssk22-specific docking site in the Pbs2 N-terminal region. The Pbs2 docking site constitutively bound the Ssk2/Ssk22 kinase domain. Docking site mutations drastically reduced the Pbs2-Ssk2/Ssk22 interaction and hampered Hog1 activation by the SLN1 branch. Fusion of the Pbs2 docking site to a different MAPKK, Ste7, allowed phosphorylation of Ste7 by Ssk2/Ssk22. Thus, the docking site contributes to both the efficiency and specificity of signaling. During these analyses, we also found a nuclear export signal and a possible nuclear localization signal in Pbs2.

Amino Acid Sequence↗

PubMed2006

TarFisDock: a web server for identifying drug targets with docking approach.

TarFisDock is a web-based tool for automating the procedure of searching for small molecule-protein interactions over a large repertoire of protein structures. It offers PDTD (potential drug target database), a target database containing 698 protein structures covering 15 therapeutic areas and a reverse ligand-protein docking program. In contrast to conventional ligand-protein docking, reverse ligand-protein docking aims to seek potential protein targets by screening an appropriate protein database. The input file of this web server is the small molecule to be tested, in standard mol2 format; TarFisDock then searches for possible binding proteins for the given small molecule by use of a docking approach. The ligand-protein interaction energy terms of the program DOCK are adopted for ranking the proteins. To test the reliability of the TarFisDock server, we searched the PDTD for putative binding proteins for vitamin E and 4H-tamoxifen. The top 2 and 10% candidates of vitamin E binding proteins identified by TarFisDock respectively cover 30 and 50% of reported targets verified or implicated by experiments; and 30 and 50% of experimentally confirmed targets for 4H-tamoxifen appear amongst the top 2 and 5% of the TarFisDock predicted candidates, respectively. Therefore, TarFisDock may be a useful tool for target identification, mechanism study of old drugs and probes discovered from natural products. TarFisDock and PDTD are available at http://www.dddc.ac.cn/tarfisdock/.

Databases, Protein↗

PubMed1990

Distance-constrained molecular docking by simulated annealing.

An optimized method based on the principle of simulated annealing is presented for determining the relative position and orientation of interacting molecules. The spatial relationships of these molecules are described by intermolecular distance constraints between specific pairs of atoms, such as found in hydrogen bonds or from experimentally determined data. The method makes use of a random walk through six rotational and translational degrees of freedom where the constituent molecules are treated as rigid bodies. Van der Waals repulsions are used only to define a lower bound on distances between constrained atom pairs within the docking procedure. A cost function comprised of purely geometric constraints is optimized via simulated annealing, in order to search for the best orientation and position of the two molecules. Our docking procedure is applied to eight serine proteinase complexes from the Brookhaven Protein Data Bank. For each simulation 100 computations were performed. A typical docking computation requires only a few seconds of CPU time on a VAXserver 3500. The influence of the number of constraints on the final docked positions was studied. The sensitivity of the docking procedure to a ligand structure which is not well defined is also addressed. Possible applications of this method include using approximate distances incorporating complete energy functions.

Aspartic Acid Endopeptidases↗

PubMed2002

Efficient docking of peptides to proteins without prior knowledge of the binding site.

Reliability in docking of ligand molecules to proteins or other targets is an important challenge for molecular modeling. Applications of the docking technique include not only prediction of the binding mode of novel drugs, but also other problems like the study of protein-protein interactions. Here we present a study on the reliability of the results obtained with the popular AutoDock program. We have performed systematical studies to test the ability of AutoDock to reproduce eight different protein/ligand complexes for which the structure was known, without prior knowledge of the binding site. More specifically, we look at factors influencing the accuracy of the final structure, such as the number of torsional degrees of freedom in the ligand. We conclude that the Autodock program package is able to select the correct complexes based on the energy without prior knowledge of the binding site. We named this application blind docking, as the docking algorithm is not able to "see" the binding site but can still find it. The success of blind docking represents an important finding in the era of structural genomics.

Algorithms↗

PubMed2003

Studying the roles of W86, E202, and Y337 in binding of acetylcholine to acetylcholinesterase using a combined molecular dynamics and multiple docking approach.

A combined molecular dynamics simulation and multiple ligand docking approach is applied to study the roles of the anionic subsite residues (W86, E202, Y337) in the binding of acetylcholine (ACh) to acetylcholinesterase (AChE). We find that E202 stabilizes docking of ACh via electrostatic interactions. However, we find no significant electrostatic contribution from the aromatic residues. Docking energies of ACh to mutant AChE show a more pronounced effect because of size/shape complementarity. Mutating to smaller residues results in poorer binding, both in terms of docking energy and statistical docking probability. Besides separating out electrostatics by turning off the partial charges from each residue and comparing it with the native, the mutations in this study are W86F, W86A, E202D, E202Q, E202A, Y337F, and Y337A. We also find that all perturbations result in a significant reduction in binding of extended ACh in the catalytically productive orientation. This effect is primarily caused by a small shift in preferred position of the quaternary tail.

Acetylcholine↗

PubMed2001

A novel approach for assessing macromolecular complexes combining soft-docking calculations with NMR data.

We present a novel and efficient approach for assessing protein-protein complex formation, which combines ab initio docking calculations performed with the protein docking algorithm BiGGER and chemical shift perturbation data collected with heteronuclear single quantum coherence (HSQC) or TROSY nuclear magnetic resonance (NMR) spectroscopy. This method, termed "restrained soft-docking," is validated for several known protein complexes. These data demonstrate that restrained soft-docking extends the size limitations of NMR spectroscopy and provides an alternative method for investigating macromolecular protein complexes that requires less experimental time, effort, and resources. The potential utility of this novel NMR and simulated docking approach in current structural genomic initiatives is discussed.

Bacterial Proteins↗

PubMed2001

Electrostatic contributions to protein-protein interactions: fast energetic filters for docking and their physical basis.

The methods of continuum electrostatics are used to calculate the binding free energies of a set of protein-protein complexes including experimentally determined structures as well as other orientations generated by a fast docking algorithm. In the native structures, charged groups that are deeply buried were often found to favor complex formation (relative to isosteric nonpolar groups), whereas in nonnative complexes generated by a geometric docking algorithm, they were equally likely to be stabilizing as destabilizing. These observations were used to design a new filter for screening docked conformations that was applied, in conjunction with a number of geometric filters that assess shape complementarity, to 15 antibody-antigen complexes and 14 enzyme-inhibitor complexes. For the bound docking problem, which is the major focus of this paper, native and near-native solutions were ranked first or second in all but two enzyme-inhibitor complexes. Less success was encountered for antibody-antigen complexes, but in all cases studied, the more complete free energy evaluation was able to identify native and near-native structures. A filter based on the enrichment of tyrosines and tryptophans in antibody binding sites was applied to the antibody-antigen complexes and resulted in a native and near-native solution being ranked first and second in all cases. A clear improvement over previously reported results was obtained for the unbound antibody-antigen examples as well. The algorithm and various filters used in this work are quite efficient and are able to reduce the number of plausible docking orientations to a size small enough so that a final more complete free energy evaluation on the reduced set becomes computationally feasible.

Amino Acids↗

PubMed2003

An all-atom solution-equilibrated model for human extrinsic blood coagulation complex (sTF-VIIa-Xa): a protein-protein docking and molecular dynamics refinement study.

Tissue factor (TF)-bound factor (F)VIIa plays a critical role in activating FX, an event that rapidly results in blood coagulation. Despite recent advances in the structural information about soluble TF (sTF)-bound VIIa and Xa individually, the atomic details of the ternary complex are not known. As part of our long-term goal to provide a structural understanding of the extrinsic blood coagulation pathway, we built an all atom solution-equilibrated model of the human sTF-VIIa-Xa ternary complex using protein-protein docking and molecular dynamics (MD) simulations. The starting structural coordinates of sTF-VIIa and Xa were derived from dynamically equilibrated solution structures. Due to the flexible nature of the light-chain of the Xa molecule, a three-stage docking approach was employed in which SP (Arg195-Lys448)/EGF2 (Arg86-Arg139), EGF1 (Asp46-Thr85) and GLA (Ala1-Lys45) domains were docked in a sequential manner. The rigid-body docking approach of the FTDOCK method in conjunction with filtering based on biochemical knowledge from experimental site-specific mutagenesis studies provided the strategy. The best complex obtained from the docking experiments was further refined using MD simulations for 3 ns in explicit water. In addition to explaining most of the known experimental site-specific mutagenesis data pertaining to sTF-VIIa, our model also characterizes likely enzyme-binding exosites on FVIIa and Xa that may be involved in the ternary complex formation. According to the equilibrated model, the 140s loop of VIIa serves as the key recognition motif for complex formation. Stable interactions occur between the FVIIa 140s loop and the FXa -strand B2 region near the sodium-binding domain, the 160 s loop and the N-terminal activation loop regions. The helical-hydrophobic stack region that connects the GLA and EGF1 domains of VIIa and Xa appears to play a potential role in the membrane binding region of the ternary complex. The proposed model may serve as a reasonable structural basis for understanding the exosite-mediated substrate recognition of sTF-VIIa and to advance understanding of the TFPI-mediated regulatory pathway of the extrinsic blood coagulation cascade.

Binding Sites↗

PubMed2000

EEG changes in 4-week-old lambs in response to castration, tail docking and mulesing.

OBJECTIVE: To interpret changes in EEG in relation to perceived pain of castration, mulesing and docking in lambs. DESIGN: Analysis of covariance (randomised block design) to determine the effects of treatment on eight bandwidths of the EEG frequency spectrum. PROCEDURE: Ninety-eight, 3- to 4-week-old lambs were subjected to one of seven treatments: castration, tail docking, mulesing, ear tagging, sham shearing, formalin injection (to induce lameness) and handling. EEG was recorded for 15 min before treatment, during treatment, and for 15 min after treatment. RESULTS: Consistently lower mean power values across all bandwidths of the EEG were found at the time of mulesing and docking than at handling and shearing (P < 0.01). Formalin injection resulted in lower power values than handling and shearing (P < 0.01). Castration had lower power values than handling and shearing. Similarly, for 15 min after treatment, mulesing and formalin injection had significantly lower power values than handling, shearing, ear tagging and castration (P < 0.05). CONCLUSION: The consistent effects associated with mulesing, docking and castration compared to handling, shearing and ear tagging suggest that mulesing at both the time of treatment and during 15 min after treatment results in a response that is similar to that of induced lameness. Docking and castration result in a response at the time of treatment that is similar to induced lameness and mulesing, but during 15 min after treatment is similar to the non-noxious control treatments. However, the depressing effects on the mean power values are the reverse of that anticipated from a previously developed pain model, highlighting the need for further research to develop this technology to evaluate pain associated with husbandry procedures.

Animal Husbandry↗

PubMed2000

Acute cortisol responses and wound healing in lambs after ring castration plus docking with or without application of a castration clamp to the scrotum.

OBJECTIVE: To test whether the cortisol response to ring castration plus docking is reduced by additional application of a castration clamp across the full width of the scrotum distal to the ring. DESIGN: A physiological study with controls. PROCEDURE: Lambs, 3 to 6 weeks of age, were castrated using a ring or ring plus castration clamp applied for 6 or 10 s and docked using a ring. Blood samples were taken before and regularly for about 4 h after treatment and analysed for plasma cortisol concentrations. The healing of the scrotal wounds was monitored for 6 weeks after castration. RESULTS: The plasma cortisol concentrations were lower only at 60 min after treatment in lambs castrated with a clamp placed on the scrotum for 10 s after ring castration and docking than in lambs castrated and docked by ring alone. Scrotal wounds healed more quickly after ring plus clamp than after ring only castration. CONCLUSIONS: The castration clamp had at most a marginal effect on the cortisol response to ring castration and docking of 3- to 6-week-old lambs, but it did seem to improve the rate of healing.

Animals↗

PubMed2004

The docking protein Gab1 is an essential component of an indirect mechanism for fibroblast growth factor stimulation of the phosphatidylinositol 3-kinase/Akt antiapoptotic pathway.

The docking protein Gab1 has been implicated as a mediator of multiple signaling pathways that are activated by a variety of receptor tyrosine kinases and cytokines. We have previously proposed that fibroblast growth factor 1 (FGF1) stimulation of tyrosine phosphorylation of Gab1 and recruitment of phosphatidylinositol (PI) 3-kinase are mediated by an indirect mechanism in which the docking protein fibroblast receptor substrate 2alpha (FRS2alpha) plays a critical role. In this report, we explore the role of Gab1 in FGF1 signaling by using mouse embryo fibroblasts (MEFs) derived from Gab1(-/-) or FRS2alpha(-/-) mice. We demonstrate that Gab1 is essential for FGF1 stimulation of both PI 3-kinase and the antiapoptotic protein kinase Akt, while FGF1-induced mitogen-activated protein kinase (MAPK) stimulation is not affected by Gab1 deficiency. To test the indirect mechanism for FGF1 stimulation of PI 3-kinase and Akt, we use a chimeric docking protein composed of the membrane targeting signal and the phosphotyrosine-binding domain of FRS2alpha fused to the C-terminal portion of Gab1, the region including the binding sites for the complement of signaling proteins that are recruited by Gab1. We demonstrate that expression of the chimeric docking protein in Gab1(-/-) MEFs rescues PI 3-kinase and the Akt responses, while expression of the chimeric docking protein in FRS2alpha(-/-) MEFs rescues stimulation of both Akt and MAPK. These experiments underscore the essential role of Gab1 in FGF1 stimulation of the PI 3-kinase/Akt signaling pathway and provide further support for the indirect mechanism for FGF1 stimulation of PI 3-kinase involving regulated assembly of a multiprotein complex.

Adaptor Proteins, Signal Transducing↗

PubMed2006

The modified docking procedure for elbow ulnar collateral ligament reconstruction: 2-year follow-up in elite throwers.

BACKGROUND: Ulnar collateral ligament injury is most common in the overhead-throwing athlete. Jobe et al published the first report of ulnar collateral ligament reconstruction in throwing athletes with a 62.5% success rate. Recently, Altchek developed a new docking technique for reconstruction of the ulnar collateral ligament. The authors report the first series using a further modification of the docking technique using a 4-strand palmaris longus graft for reconstruction of the ulnar collateral ligament. HYPOTHESIS: The modified docking technique yields a high rate of successful return to preinjury level of competition in elite baseball players. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The authors retrospectively reviewed 25 elite professional or scholarship collegiate baseball players who underwent elbow ulnar collateral ligament reconstruction using the modified docking procedure with a minimum 2-year follow-up. RESULTS: Twenty-three of 25 (92%) were able to return to their preinjury levels of competition. The mean time to return was 11.5 months (range, 10-16 months). Complications included 1 transient postoperative ulnar nerve neurapraxia and 1 stress fracture of the ulnar bone bridge that occurred at 14 months postoperatively, after a full return to pitching. CONCLUSION: The modified docking technique yields highly successful return to preinjury level of competition rates (92%) in a select group of elite baseball players.

Adult↗

PubMedDate not supplied

Assessing workload through physiological measurements in bus drivers using an automated system during docking.

The aim of the experiment was to test the effect of an automated system of bus docking on drivers' mental workload. Reduced workload is thought to be brought about by helping the driver to maneuver, as he or she is required only to monitor proper functioning of the system. However, the true impact of the system on drivers must be studied to guarantee good acceptance and minimal distraction from traffic. Workload was estimated by electrodermal activity recording while drivers tested 5 scenarios involving (or not involving) the docking system. Results showed that docking precision was improved when the system was used. When drivers monitored the functioning of the system, their workload was higher than that observed during manual docking; however, reduced workload was evidenced after a learning process. The docking system was also shown to increase workload in the event of dysfunction, especially when drivers had to take over control. Despite this particular situation, and after habituation, such a system could be integrated into buses to improve safety during boarding and egress.

Automation↗