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PubMed1992

A robust and efficient automated docking algorithm for molecular recognition.

A completely automated method is described for determining the most likely mode of binding of two (macro)molecules from the knowledge of their three-dimensional structures alone. The method is based on well-known graph theoretical techniques and has been used successfully to determine and rationalize the binding of a number of known macromolecular complexes. In this article we present results for a special case of the general molecular recognition problem--given the information concerning the particular atoms involved in the binding for one of the molecules, the algorithm can correctly identify the corresponding (contacting) atoms of the other molecule. The approach used can be easily extended to the general molecular recognition problem and requires the extraction of maximal common subgraphs. In these studies the docking of the macromolecules was achieved without the aid of computer graphics or other visual aids. The algorithm has been used to determine the correct mode of binding of a protein antigen to an antibody in approximately 100 min on a DEC micro VAX 3600.

Algorithms↗
PubMed2004

The acroplaxome is the docking site of Golgi-derived myosin Va/Rab27a/b- containing proacrosomal vesicles in wild-type and Hrb mutant mouse spermatids.

Acrosome biogenesis involves the transport and fusion of Golgi-derived proacrosomal vesicles along the acroplaxome, an F-actin/keratin 5-containing cytoskeletal plate anchored to the spermatid nucleus. A significant issue is whether the acroplaxome develops in acrosomeless mutant mice. Male mice with a Hrb null mutation are infertile and both spermatids and sperm are round-headed and lack an acrosome. Hrb, a protein that contains several NPF motifs (Asn-Pro-Phe) and interacts with proteins with Eps15 homology domains, is regarded as critical for the docking and/or fusion of Golgi-derived proacrosomal vesicles. Here we report that the lack of an acrosome in Hrb mutant spermatids does not prevent the development of the acroplaxome. Yet the acroplaxome in the mutant contains F-actin but is deficient in keratin 5. We also show that the actin-based motor protein myosin Va and its receptor, Rab27a/b, known to be involved in vesicle transport, are present in the Golgi and Golgi-derived proacrosomal vesicles in wild-type and Hrb mutant mouse spermatids. In the Hrb mutant, myosin-Va-bound proacrosome vesicles tether to the acroplaxome, where they flatten and form a flat sac, designated pseudoacrosome. As spermiogenesis advances, round-shaped spermatid nuclei of the mutant display several nuclear protrusions, designated nucleopodes. Nucleopodes are consistently found at the acroplaxome- pseudoacrosome site. Our findings support the interpretation that the acroplaxome provides a focal point for myosin-Va/ Rab27a/b-driven proacrosomal vesicles to accumulate, coalesce, and form an acrosome in wild-type spermatids and a pseudoacrosome in Hrb mutant spermatids. We suggest that nucleopodes develop at a site where a keratin 5-deficient acroplaxome may not withstand tension forces operating during spermatid nuclear shaping.

Acrosome↗
PubMed2000

Ceramide binds to the CaLB domain of cytosolic phospholipase A2 and facilitates its membrane docking and arachidonic acid release.

Excessive production of eicosanoids is characteristic of many inflammatory diseases. In this study we show that ceramide, which is an early messenger of inflammatory cytokine action, exerts a dual effect on the cytosolic phospholipase A2 (cPLA2), the rate-limiting enzyme in arachidonic acid release and subsequent eicosanoid formation. Stimulation of renal mesangial cells with exogenous short-chain ceramide analogs for 30 and 60 min leads to a concentration-dependent increase in arachidonic acid release that is not blocked by specific inhibitors of mitogen-activated protein kinase pathways. This suggests that these established upstream activators of cPLA2 are not involved in ceramide-induced arachidonic acid release. By use of photoactivatable ceramide analogs, D- and L-[125I]3-trifluoromethyl-3-(m-iodophenyl)diazirine-ceramides (TID-ceramides), we observed a direct interaction of ceramide with cPLA2. This interaction was independent of the absolute configuration as D- and L-TID-ceramide were equally effective in binding to cPLA2. Moreover, recombinant CaLB domain of cPLA2 as well as a mutant deficient in the connecting 'hinge' domain of cPLA2, efficiently bound D- and L-TID-ceramides, whereas the catalytic domain did not interact with TID-ceramides. In vitro binding assays reveal that stearoyl-arachidonyl-phosphatidylcholine (SAPC)-liposomes containing increasing mol% of ceramide lead to an increased association of recombinant cPLA2 to the liposomes. Furthermore, measurement of cPLA2 activity in vitro shows that the presence of SAPC-liposomes resulted in only weak cPLA2 activity. However, the activity dramatically increases by addition of ceramide to the liposomes. Furthermore, liposomes containing SAPC and sphingomyelin resulted in no better substrate than SAPC liposomes, unless bacterial sphingomyelinase was added to generate ceramide, which then causes a marked increase in cPLA2 activity. These results demonstrate that ceramide can interact directly with cPLA2 via the CaLB domain and thereby serves as a membrane-docking device that facilitates cPLA2 action in inflammatory diseases.

Animals↗
PubMed2002

Neurons and plaques of Alzheimer's disease patients highly express the neuronal membrane docking protein p42IP4/centaurin alpha.

The protein p42(IP4) (also called centaurin alpha), identified as a brain-specific InsP4/PtdInsP3 (PIP3)-binding protein, has been shown to be localized in human brain, specifically expressed in neurons. Several casein kinases have been found to be involved in Alzheimer's disease (AD) pathology. Since casein kinase I was reported to possess a binding domain for p42(IP4), we here investigated the expression and localization of p42(IP4) in AD brains. In cortical neurons of AD brains intracellular immunostaining for p42(IP4) exceeded the level seen in these neurons of normal brain. Statistically, significantly more p42(IP4)-immunoreactive neurons were found in temporal and angular cortex of AD patients as compared to control brain. Mostly impressively, neuritic plaques displayed a very prominent signal. Thus, we suggest that the up-regulated p42(IP4) in AD neurons may serve as a docking protein to recruit signaling molecules such as different subtypes of casein kinase I to the plasma membrane. This is the first indication for a functional interaction of these protein in possible neuronal damage. Therefore proteins such as p42(IP4), central players in signaling, may be appropriate targets for preventing neurodegenerative processes.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Activation of Ras in neurons modifies synaptic vesicle docking and release.

We have recently demonstrated that constitutive activation of Ha-Ras in differentiated neurons induces structural remodeling of both axons and dendrites in a transgenic mouse model (referred as synRas mice). Here we show that this activation of neuronal Ras enhances docking of synaptic vesicles to active zones, thereby leading to an increase in the size of the readily releasable pool of vesicles, while the size of the total pool of synaptic vesicles remained unchanged. The morphological phenotype was associated with corresponding increases in the probability of glutamate release as revealed by changes in short-term synaptic plasticity. We, therefore, conclude that neuronal Ras activity contributes to the regulation of synaptic plasticity in adult mammalian brain at the presynaptic level.

Animals↗
PubMed1999

Genetic evidence for an equilibrium between docked and undocked vesicles.

By using the shibire mutation to block endocytosis in a temperature-dependent fashion, we have manipulated the number of synaptic vesicles in a nerve terminal and have observed a remarkable proportionality of the number of quanta released to the size of the total vesicle pool. In the experiments described below we determine that approximately 0.3% of the vesicle pool is released per stimulus. The data suggest that the pool of readily releasable docked vesicles does not represent the saturation of a limiting number of release sites, but instead represents a subset of vesicles that is in equilibrium with the larger pool of vesicles. Before presenting this data and the significance of the finding for the regulation of neurotransmission, we will briefly review the use of Drosophila genetics as a tool for dissecting synaptic transmission.

Animals↗
PubMed2025

Nanoscopy Reveals Heparan Sulfate Clusters as Docking Sites for SARS-CoV-2 Attachment and Entry.

Virus entry is thought to involve binding a unique receptor for cell attachment and cytosolic entry. For SARS-CoV-2 underlying the COVID-19 pandemic, angiotensin-converting enzyme 2 (ACE2) is widely assumed as the receptor. Using advanced light microscopy to resolve individual virions and receptors, we found instead that heparan sulfate (HS), not ACE2, mediates SARS-CoV-2 cell-surface attachment and subsequent endocytosis. ACE2 functions only downstream of HS to enable viral genome expression. Instead of binding single HS molecules that electrostatically interact with viral surface proteins weakly, SARS-CoV-2 binds clusters of ~6-137 HS molecules projecting 60-410 nm above the plasma membrane. These tall, HS-rich clusters, present at about one per 6 μm2, act as docking sites for viral attachment. Blocking HS binding with the clinically used HS-binding agent pixantrone strongly inhibited the clinically relevant SARS-CoV-2 Omicron JN.1 subvariant from attaching to and infecting human airway cells. This work establishes a revised entry paradigm in which HS clusters mediate SARS-CoV-2 attachment and endocytosis, with ACE2 acting downstream, thereby identifying HS interactions as a key anti-COVID-19 strategy. This paradigm and its therapeutic implications may apply broadly beyond COVID-19 because, analogous to SARS-CoV-2, HS binds many other viruses but is only considered an attachment regulator.

Journal Article↗
PubMed1992

A lock-docking oligo(dT) primer for 5' and 3' RACE PCR.

We describe a method that can be used to obtain and sequence 3' and 5' ends of cDNA transcripts directly from PCR products. The method employs a modified oligo(dT) primer that enables it to "lock-dock" at the junction of gene-specific cDNA sequence and a natural (3') or appended (5') poly(A) tail. As a result, discrete, first-round PCR products are obtained that are easily isolated and sequenced directly.

Animals↗
PubMed2006

Exploring the interaction between the protein kinase A catalytic subunit and caveolin-1 scaffolding domain with shotgun scanning, oligomer complementation, NMR, and docking.

The techniques of phage-displayed homolog shotgun scanning, oligomer complementation, NMR secondary structure analysis, and computational docking provide a complementary suite of tools for dissecting protein-protein interactions. Focusing these tools on the interaction between the catalytic sub-unit of protein kinase A (PKAcat) and caveolin-1 scaffolding domain (CSD) reveals the first structural model for the interaction. Homolog shotgun scanning varied each CSD residue as either a wild-type or a homologous amino acid. Wild-type to homolog ratios from 116 different homologous CSD variants identified side-chain functional groups responsible for precise contacts with PKAcat. Structural analysis by NMR assigned an alpha-helical conformation to the central residues 84- 97 of CSD. The extensive mutagenesis data and NMR secondary structure information provided constraints for developing a model for the PKAcat-CSD interaction. Addition of synthetic CSD to phage-displayed CSD resulted in oligomer complementation, or enhanced binding to PKAcat. Together with previous experiments examining the interaction between CSD and endothelial nitric oxide synthase (eNOS), the results suggest a general oligomerization-dependent enhancement of binding between signal transducing enzymes and caveolin-1.

Binding Sites↗
PubMed1999

Function of the central domain of streptokinase in substrate plasminogen docking and processing revealed by site-directed mutagenesis.

The possible role of the central beta-domain (residues 151-287) of streptokinase (SK) was probed by site-specifically altering two charged residues at a time to alanines in a region (residues 230-290) previously identified by Peptide Walking to play a key role in plasminogen (PG) activation. These mutants were then screened for altered ability to activate equimolar "partner" human PG, or altered interaction with substrate PG resulting in an overall compromised capability for substrate PG processing. Of the eight initial alanine-linker mutants of SK, one mutant, viz. SK(KK256.257AA) (SK-D1), showed a roughly 20-fold reduction in PG activator activity in comparison to wild-type SK expressed in Escherichia coli (nSK). Five other mutants were as active as nSK, with two [SK(RE248.249AA) and SK(EK281.282AA), referred to as SK(C) and SK(H), respectively] showing specific activities approximately one-half and two-thirds, respectively, that of nSK. Unlike SK(C) and SK(H), however, SK(D1) showed an extended initial delay in the kinetics of PG activation. These features were drastically accentuated when the charges on the two Lys residues at positions 256 and 257 of nSK were reversed, to obtain SK(KK256.257EE) [SK(D2)]. This mutant showed a PG activator activity approximately 10-fold less than that of SK(D1). Remarkably, inclusion of small amounts of human plasmin (PN) in the PG activation reactions of SK(D2) resulted in a dramatic, PN dose-dependent rejuvenation of its PG activation capability, indicating that it required pre-existing PN to form a functional activator since it could not effect active site exposure in partner PG on its own, a conclusion further confirmed by its inability to show a "burst" of p-nitrophenol release in the presence of equimolar human PG and p-nitrophenyl guanidino benzoate. The steady-state kinetic parameters for HPG activation of its 1:1 complex with human PN revealed that although it could form a highly functional activator once "supplied" with a mature active site, the Km for PG was increased nearly eightfold in comparison to that of nSK-PN. SK mutants carrying simultaneous two- and three-site charge-cluster alterations, viz., SK(RE24249AA:EK281.282AA) [SK(CH)], SK(EK272.273AA;EK281.282AA) [SK(FH)], and SK(RE248.249AA;EK272.273AA:EK281.282AA+ ++) [SK(CFH)], showed additive/synergistic influence of multiple charge-cluster mutations on HPG activation when compared to the respective "single-site" mutants, with the "triple-site" mutant [SK(CFH)] showing absolutely no detectable HPG activation ability. Nevertheless, like the other constructs, the double- and triple-charge cluster mutants retained a native like affinity for complexation with partner PG. Their overall structure also, as judged by far-ultraviolet circular dichroism, was closely similar to that of nSK. These results provide the first experimental evidence for a direct assistance by the SK beta-domain in the docking and processing of substrate PG by the activator complex, a facet not readily evident probably because of the flexibility of this domain in the recent X-ray crystal structure of the SK-plasmin light chain complex.

Amino Acid Sequence↗
PubMed1999

Comparison of protein-protein interactions in serine protease-inhibitor and antibody-antigen complexes: implications for the protein docking problem.

The protein-protein interaction energy of 12 nonhomologous serine protease-inhibitor and 15 antibody-antigen complexes is calculated using a molecular mechanics formalism and dissected in terms of the main-chain vs. side-chain contribution, nonrotameric side-chain contributions, and amino acid residue type involvement in the interface interaction. There are major differences in the interactions of the two types of protein-protein complex. Protease-inhibitor complexes interact predominantly through a main-chain-main-chain mechanism while antibody-antigen complexes interact predominantly through a side-chain-side-chain or a side-chain-main-chain mechanism. However, there is no simple correlation between the main-chain-main-chain interaction energy and the percentage of main-chain surface area buried on binding. The interaction energy is equally effected by the presence of nonrotameric side-chain conformations, which constitute approximately 20% of the interaction energy. The ability to reproduce the interface interaction energy of the crystal structure if original side-chain conformations are removed from the calculation is much greater in the protease-inhibitor complexes than the antibody-antigen complexes. The success of a rotameric model for protein-protein docking appears dependent on the extent of the main-chain-main-chain contribution to binding. Analysis of (1) residue type and (2) residue pair interactions at the interface show that antibody-antigen interactions are very restricted with over 70% of the antibody energy attributable to just six residue types (Tyr > Asp > Asn > Ser > Glu > Trp) in agreement with previous studies on residue propensity. However, it is found here that 50% of the antigen energy is attributable to just four residue types (Arg = Lys > Asn > Asp). On average just 12 residue pair interactions (6%) contribute over 40% of the favorable interaction energy in the antibody-antigen complexes, with charge-charge and charge/polar-tyrosine interactions being prominent. In contrast protease inhibitors use a diverse set of residue types and residue pair interactions.

Antigen-Antibody Complex↗
PubMed2000

A new model for 20-hydroxyecdysone and dibenzoylhydrazine binding: a homology modeling and docking approach.

The ecdysone receptor (ECR), a nuclear transcription factor controlling insect development, is a novel target for insecticides such as dibenzoylhydrazines with low environmental and toxicological impacts. To understand the high selectivity of such synthetic molecules toward ECR, two homology models of the Chironomus tentans ECR ligand-binding domain (LDB) have been constructed by taking as templates the known LBD crystal structures of the retinoic acid and vitamin D receptors. Docking of 20-hydroxyecdysone (20E) and dibenzoylhydrazines to the receptor suggests a novel superposition of the natural and synthetic molecules; the N-tert-butyl substituent of the dibenzoylhydrazines extends significantly beyond the 20E volume. Our ECR-LBD protein models rationalize how 20E and dibenzoylhydrazines interact with the ligand-binding pocket. The homology model complexes provide new insights that can be exploited in the rational design of new environmentally safe insecticides.

Amino Acid Sequence↗
PubMed2004

NMR and molecular dynamics studies of an autoimmune myelin basic protein peptide and its antagonist: structural implications for the MHC II (I-Au)-peptide complex from docking calculations.

Experimental autoimmune encephalomyelitis can be induced in susceptible animals by immunodominant determinants of myelin basic protein (MBP). To characterize the molecular features of antigenic sites important for designing experimental autoimmune encephalomyelitis suppressing molecules, we report structural studies, based on NMR experimental data in conjunction with molecular dynamic simulations, of the potent linear dodecapeptide epitope of guinea pig MBP, Gln74-Lys75-Ser76-Gln77-Arg78-Ser79-Gln80-Asp81-Glu82-Asn83-Pro84-Val85 [MBP(74-85)], and its antagonist analogue Ala81MBP(74-85). The two peptides were studied in both water and Me(2)SO in order to mimic solvent-dependent structural changes in MBP. The agonist MBP(74-85) adopts a compact conformation because of electrostatic interactions of Arg78 with the side chains of Asp81 and Glu82. Arg78 is 'locked' in a well-defined conformation, perpendicular to the peptide backbone which is practically solvent independent. These electrostatic interactions are, however, absent from the antagonist Ala81MBP(74-85), resulting in great flexibility of the side chain of Arg78. Sequence alignment of the two analogues with several species of MBP suggests a critical role for the positively charged residue Arg78, firstly, in the stabilization of the local microdomains (epitopes) of the integral protein, and secondly, in a number of post-translational modifications relevant to multiple sclerosis, such as the conversion of charged arginine residues to uncharged citrullines. Flexible docking calculations on the binding of the MBP(74-85) antigen to the MHC class II receptor site I-A(u) using haddock indicate that Gln74, Ser76 and Ser79 are MHC II anchor residues. Lys75, Arg78 and Asp81 are prominent, solvent-exposed residues and, thus, may be of importance in the formation of the trimolecular T-cell receptor-MBP(74-85)-MHC II complex.

Alanine↗
PubMed2004

After chitin docking, toxicity of Kluyveromyces lactis zymocin requires Saccharomyces cerevisiae plasma membrane H+-ATPase.

Zymocin, a three-subunit (alpha beta gamma) toxin complex from Kluyveromyces lactis, imposes a cell cycle block on Saccharomyces cerevisiae. Phenotypic analysis of the resistant kti10 mutant implies a membrane defect, suggesting that KTI10 represents a gene involved early in the zymocin response. Consistently, KTI10 is shown here to be allelic to PMA1 encoding H(+)-ATPase, a plasma membrane H(+) pump vital for membrane energization (Delta Psi). Like pma1 mutants, kti10 cells lose viability at low pH, indicating a pH homeostasis defect, and resist the antibiotic hygromycin B, uptake of which is known to be Pma1 and Delta Psi sensitive. Similar to kti10 cells, pma1 mutants with reported H(+) pump defects survive in the presence of exozymocin but do not resist endogenous expression of its lethal gamma-toxin subunit. Based on DNA sequence data, kti10 cells are predicted to produce a malfunctional Pma1 variant with expression levels that are normal. Intriguingly, zymocin protection of kti10 cells is suppressed by excess H(+), a scenario ineffective in bypassing resistance of chitin or toxin target mutants. Together with unaltered zymocin docking and gamma-toxin import events in kti10 cells, our data suggest that Pma1's role in zymocin action is likely to involve activation of gamma-toxin in a step following its cellular uptake.

Alleles↗
PubMed1989

Feminist friendship: Isabel Hampton Robb, Lavinia Lloyd Dock and Mary Adelaide Nutting.

Three nurses who met at the Johns Hopkins School of Nursing were the architects of professional nursing education and the founders of the major professional organizations in nursing: Isabel Hampton Robb, Lavinia Lloyd Dock and Mary Adelaide Nutting. Their relationship was an important part of the context in which feminism, social reform and nursing came together at the turn of the century. This paper explores the social context that structured their professional interests as well as their personal relationships.

Education, Nursing↗
PubMed2005

Rab11 promotes docking and fusion of multivesicular bodies in a calcium-dependent manner.

Multivesicular bodies (MVBs) are membranous structures within 60-100 nm diameter vesicles accumulate. MVBs are generated after invagination and pinching off of the endosomal membrane in the lumen of the vacuole. In certain cell types, fusion of MVBs with the plasma membrane results in the release of the internal vesicles called exosomes. In this report we have examined how an increase in cytosolic calcium affects the development of MVBs and exosome release in K562 cells overexpressing GFP-Rab11 wt or its mutants. In cells overexpressing the Rab11Q70 L mutant or Rab11 wt, an increase in the cytosolic calcium concentration induced by monensin caused a marked enlargement of the MVBs. This effect was abrogated by the membrane permeant calcium chelator BAPTA-AM. We also examined the behavior of MVBs in living cells by time lapse confocal microscopy. Many MVBs, decorated by wt or Q70L mutant GFP-Rab11, were docked and ready to fuse in the presence of a calcium chelator. This observation suggests that Rab11 is acting in the tethering/docking of MVBs to promote homotypic fusion, but that the final fusion reaction requires the presence of calcium. Additionally, a rise in intracellular calcium concentration enhanced exosome secretion in Rab11 wt overexpressing cells and reversed the inhibition of the mutants. The results suggest that both Rab11 and calcium are involved in the homotypic fusion of MVBs.

Calcium↗
PubMed2002

Molecular docking of competitive phosphodiesterase inhibitors.

Mammalian phosphodiesterases types 3 and 4 (PDE3 and PDE4) hydrolyze cAMP and are essential for the regulation of this intracellular second messenger. These enzymes share structural and biochemical similarities, but each can be distinguished by its sensitivity to isoenzyme-specific, substrate-competitive inhibitors. We present a model configuration for the PDE4 substrate (cAMP) and a PDE4-specific inhibitor (rolipram) within the active site of the enzyme. The docked models were also used to examine the structural consequences of mutations that confer resistance to rolipram and other PDE4-specific inhibitors. The proposed rolipram-binding configuration is consistent with the substrate-competitive nature of inhibition and also provides a structural basis for the observed specificity of binding to the R- versus S-enantiomer. For mutations that render the enzyme rolipram-insensitive, there was generally an inverse relationship between the magnitude of the drug resistance and the distance of the altered residue from the predicted binding site. We observed a direct correlation between the net loss of protein residue interactions (van der Waals contacts and hydrogen bond interactions) and the degree of rolipram resistance. The positions of several drug sensitivity-determinant residues define a surface leading to the substrate- and drug-binding sites, suggesting a possible approach channel leading to the enzyme active site. The binding of other PDE4 inhibitors (high- and low-affinity) was also modeled and used to predict the involvement of residues that were not previously implicated in pharmacological interactions.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2006

The nucleosomal surface as a docking station for Kaposi's sarcoma herpesvirus LANA.

Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) mediates viral genome attachment to mitotic chromosomes. We find that N-terminal LANA docks onto chromosomes by binding nucleosomes through the folded region of histones H2A-H2B. The same LANA residues were required for both H2A-H2B binding and chromosome association. Further, LANA did not bind Xenopus sperm chromatin, which is deficient in H2A-H2B; chromatin binding was rescued after assembly of nucleosomes containing H2A-H2B. We also describe the 2.9-angstrom crystal structure of a nucleosome complexed with the first 23 LANA amino acids. The LANA peptide forms a hairpin that interacts exclusively with an acidic H2A-H2B region that is implicated in the formation of higher order chromatin structure. Our findings present a paradigm for how nucleosomes may serve as binding platforms for viral and cellular proteins and reveal a previously unknown mechanism for KSHV latency.

Amino Acid Substitution↗