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At least 847 records · Page 47Linked to original sources
PubMed2001

Thermostabilization by replacement of specific residues with lysine in a Bacillus alkaline cellulase: building a structural model and implications of newly formed double intrahelical salt bridges.

An alkaline, mesophilic endo-1,4-beta-glucanase from alkaliphilic Bacillus sp. strain KSM-64 was significantly thermostabilized by replacement of both Asn179 and Asp194 with lysine by site-directed mutagenesis. Structural remodeling of the mutant enzyme newly generated by the double mutation suggested that Glu175-->Lys179 and Glu190-->Lys194 were the most plausible ion pairs, both of which involved side chains at the i and i + 4 positions on the alpha(4)-helix from Glu175 to Ser195. By molecular dynamics simulations, the N(zeta) hydrogens of Lys179 and Lys194 were found to coordinate with the carbonyl O(varepsilon1) and O(varepsilon2) of Glu175 and the carbonyl O(varepsilon1) of Glu190, respectively, with distances of around 2 A for all. These results confirm that the formation of these double intrahelical ion pairs (salt bridges) is responsible for the thermostabilization by the double mutation.

Alkalies↗
PubMed1994

A structural model of the tetrodotoxin and saxitoxin binding site of the Na+ channel.

Biophysical evidence has placed the binding site for the naturally occurring marine toxins tetrodotoxin (TTX) and saxitoxin (STX) in the external mouth of the Na+ channel ion permeation pathway. We developed a molecular model of the binding pocket for TTX and STX, composed of antiparallel beta-hairpins formed from peptide segments of the four S5-S6 loops of the voltage-gated Na+ channel. For TTX the guanidinium moiety formed salt bridges with three carboxyls, while two toxin hydroxyls (C9-OH and C10-OH) interacted with a fourth carboxyl on repeats I and II. This alignment also resulted in a hydrophobic interaction with an aromatic ring of phenylalanine or tyrosine residues for the brainII and skeletal Na+ channel isoforms, but not with the cysteine found in the cardiac isoform. In comparison to TTX, there was an additional interaction site for STX through its second guanidinium group with a carboxyl on repeat IV. This model satisfactorily reproduced the effects of mutations in the S5-S6 regions and the differences in affinity by various toxin analogs. However, this model differed in important ways from previously published models for the outer vestibule and the selectivity region of the Na+ channel pore. Removal of the toxins from the pocket formed by the four beta-hairpins revealed a structure resembling a funnel that terminated in a narrowed region suitable as a candidate for the selectivity filter of the channel. This region contained two carboxyls (Asp384 and Glu942) that substituted for molecules of water from the hydrated Na+ ion. Simulation of mutations in this region that have produced Ca2+ permeation of the Na+ channel created a site with three carboxyls (Asp384, Glu942, and Glu1714) in proximity.

Amino Acid Sequence↗
PubMed2003

A structural model that explains the effects of hyperglycemia on collagenolysis.

Prior investigations into the effects hyperglycemia on collagen degradation have yielded conflicting results. We present a new formalism for understanding the biochemistry of collagenolysis and the effects of hyperglycemia on collagen degradation. The analysis is based on an understanding of environments that affect the conformational stability of collagen. We suggest that collagen can exist in two distinct conformational states-a native state and a vulnerable state. Vulnerable collagen corresponds to a non-native conformation where partially unfolded regions near collagenase cleavage sites enable collagenases to efficiently degrade collagen. Theoretical calculations on collagen-like model peptides suggest that relatively short periods of hyperglycemia can alter the equilibrium distribution of states to favor vulnerable states of collagen. These data provide new insights into the mechanism of collagenolysis and resolve apparently discrepant experimental data on the effects of hyperglycemia on collagen degradation.

Animals↗
PubMed2005

Functional insights from the structural modelling of a small Fe-hydrogenase.

Recently, a novel Fe-hydrogenase from a high rate of hydrogen producing Enterobacter cloacae strain IIT-BT08 was identified and partially characterized. This 147 residue protein was found to be much smaller than previously known Fe-hydrogenases, yet retaining a high catalytic activity. We predicted the structure of this protein and found it to be structurally similar to one of the two sub-domains containing the catalytic H-cluster so far jointly present in all other Fe-hydrogenases. This novel architecture allows a tentative explanation of protein function with the high rate of catalytic activity being due to a missing regulatory sub-domain, presumably allowing higher enzymatic activity at the cost of greater exposure to oxygen inactivation. This new insight may improve our understanding of the molecular and functional organization of other, more complex Fe-hydrogenases.

Amino Acid Sequence↗
PubMed2006

Ribosome dynamics: insights from atomic structure modeling into cryo-electron microscopy maps.

Single-particle cryo-electron microscopy (cryo-EM) is the method of choice for studying the dynamics of macromolecular machines both at a phenomenological and, increasingly, at the molecular level, with the advent of high-resolution component X-ray structures and of progressively improving fitting algorithms. Cryo-EM has shed light on the structure of the ribosome during the four steps of translation: initiation, elongation, termination, and recycling. Interpretation of cryo-EM reconstructions of the ribosome in quasi-atomic detail reveals a picture in which the ribosome uses RNA not only to catalyze chemical reactions, but also as a means for signal transduction over large distances.

Computer Simulation↗
PubMed2003

Towards an integrated, structural model of psychiatric rehabilitation.

In the past two decades, the number of principles and approaches that have been touted as psychiatric rehabilitation have overwhelmed the service provider. As a result, the field seems to be bombarded by contradictory ideas. In this paper, I seek to resolve this problem by providing an overview of psychiatric rehabilitation in terms of four key structures: goals (the reasons why people with psychiatric disabilities seek rehabilitation), strategies (the tools which service providers might use to help consumers reach their goals), settings (the places in which providers and consumers use these tools), and roles (the variety of professional and personal backgrounds which influence providers in carrying out their duties). In this paper, I review the research literature that has identified relevant examples of each of these structural dimensions. This description of psychiatric rehabilitation is based on a two-factor model of the life challenges that arise from mental illness: the disabilities produced by the disease and the loss of opportunity that result from stigma and discrimination. The paper also includes a brief discussion of the two-factor model.

Cognition Disorders↗
PubMed1988

Electron microscopy and structural model of human fibronectin receptor.

Highly-purified human fibronectin receptor (a heterodimer of two distinct subunits, alpha and beta) was studied using electron microscopy and a variety of preparative procedures. It was found that the receptor consists of a globular head approximately 80 by 120 A and two tails about 20 A thick and 180-200 A long. The whole complex is approximately 280 A long. At low concentrations of detergent the receptor forms doublets, triplets or rosettes associated with the tails which possess the transmembrane portion of the molecule. Computer-assisted structure prediction using the published amino acid sequence of both subunits showed differences in the secondary structure of the tails, the alpha-tail being rich in beta-strands, the beta-tail having five cysteine-rich repeats analogous to the EGF-like repeats of laminin. Estimates of the length of the tails from the predicted structure conformed well with the dimensions obtained from electron micrographs.

Amino Acid Sequence↗
PubMed1984

Laminin, proteoglycan, nidogen and collagen IV: structural models and molecular interactions.

Major components of basement membranes, including collagen IV, laminin, heparan sulphate proteoglycan and nidogen, were isolated from the matrix of the EHS sarcoma. The purified components were analysed for their domain structure and for the participation of distinct domains in molecular interactions and cell binding. Collagen IV consists of four domains which have triple helical or non-collagenous structures. Self-assembly of the protein into a network-like organization occurs by specific interactions between N-terminal triple helical segments and between the C-terminal globules. Cell binding requires a central triple helical segment. Laminin has the shape of an asymmetrical cross; different globular domains within this structure mediate binding to proteoglycan and to cells. The proteoglycan consists of four heparan sulphate chains attached to a small protein core. These chains have the potential to bind laminin, fibronectin and collagen IV. Nidogen was isolated in several molecular forms which showed either self-aggregation or binding to laminin.

Animals↗
PubMed2006

Zirconium-substituted isopolytungstates: structural models for zirconia-supported tungsten catalysts.

The synthesis and characterization of a series of mixed W-Zr polynuclear Lindqvist-type complexes, deriving from hexatungstate [W6O19]2-, are described in this work. This family of compounds is built from {W5O18Zr}2- moieties as shown by the X-ray structures of the monomeric [W5O18Zr(H2O)(3-n)(DMSO)n]2- (n = 1 and 2) and dimeric [{W5O18Zr(mu-OH)}2]6- anions. A comprehensive spectroscopic study (183W NMR, FTIR, Raman, EXAFS, and EPR) of these compounds is presented. The goal of incorporating Zr(IV) cations into an oxotungstic core is to obtain spectroscopic models that could mimic the interactions that develop in supported catalysts between the active phase and the supporting oxide. This work tends to show that these molecular compounds can be regarded as soluble structural analogues of WOx/ZrO2 catalysts, which are interesting candidates for the skeletal isomerization of light n-alkanes.

Journal Article↗
PubMed2003

A distributed, collaborative, structuring model for a clinical-guideline digital-library.

The Digital Electronic Guideline Library (DeGeL) is a Web-based framework and a set of distributed tools that facilitate gradual conversion of clinical guidelines from free text, through semi-structured text, to a fully structured, executable representation. Thus, guidelines exist in a hybrid, multiple-format representation The three formats support increasingly sophisticated computational tasks. The tools perform semantic markup, classification, search, and browsing, and support computational modules that we are developing, for run-time application and retrospective quality assessment. We describe the DeGeL architecture and its collaborative-authoring authorization model, which is based on (1) multiple medical-specialty authoring groups, each including a group manager who controls group authorizations, and (2) a hierarchical authorization model based on the different functions involved in the hybrid guideline-specification process. We have implemented the core modules of the DeGeL architecture and demonstrated distributed markup and retrieval using the knowledge roles of two guidelines ontologies (Asbru and GEM). We are currently evaluating several of the DeGeL tools.

Computer Communication Networks↗
PubMed2000

Structural model of human alpha1-microglobulin: proposed scheme for the interaction with the Gla domain of anticoagulant protein C.

Alpha1-microglobulin (alpha1m) is a small glycoprotein with immunomodulatory properties. It is a member of the lipocalin family, a group of proteins that exhibit a well-conserved three-dimensional structure despite low sequence identity and that are known to bind small hydrophobic ligands. The types of ligands carried by alpha1m are still unknown, but it is known that this protein has yellow-brown chromophores attached to three lysines at position 92, 118 and 130. Alpha1m has one unpaired cysteine residue (Cys 34) that can form a disulphide bond with other proteins that also possess an exposed free unpaired cysteine. For instance, alpha1m interacts with the protein C (PC) Gla domain containing the Arg9Cys or Ser12Cys substitution. In order to gain insights about the alpha1m molecule and analyze the intriguing alpha1m-Gla domain interaction, it was decided to use bioinformatics. The three-dimensional structures of alpha1m and PC Gla domain were predicted. Alpha1m Cys 34 is solvent exposed and located near the entrance of the ligand-binding pocket. The chromophore-carrying lysines are found buried into the pocket, and the area around the entrance of this cavity displays about 10 positively charged residues. This electropositive region in alpha1m complements the essentially electronegative Gla domain and may play a role during intermolecular interactions. In addition, a few hydrophobic residues surround alpha1m Cys 34 and could be of importance during its interaction with macromolecular ligands.

Amino Acid Sequence↗
PubMed1998

Structural models of the bovine papillomavirus E5 protein.

The bovine papillomavirus E5 protein is thought to be a type II integral membrane protein that exists as a disulfide-linked homodimer in transformed cells. Polarized-infrared measurements show that the E5 dimer in membrane bilayers is largely alpha-helical and has a transmembrane orientation. Computational searches of helix-helix conformations reveal two possible low-energy dimer structures. Correlation of these results with previous mutagenesis studies on the E5 protein suggests how the E5 dimer may serve as a molecular scaffold for dimerization and ligand-independent activation of the PDGF-beta receptor. We propose that on each face of the E5 dimer a PDGF-beta receptor molecule interacts directly with Gln17 from one E5 monomer and with Asp33 from the other E5 monomer. This model accounts for the requirement of Gln17 and Asp33 for complex formation and explains genetic results that dimerization of the E5 protein is essential for cell transformation.

Algorithms↗
PubMedDate not supplied

[Evaluation of certain structural models of pre-transition phenomena in liquid-crystal lipid systems].

The material on optical modelling of pretransition processes in liquid crystalline hydrated lipid phases is presented. Results of estimation of the model of monoclinic phase formation are in the poorer agreement with X-ray diffraction data than the model of kinks appearance in the aliphatic core of layers. Arguments are presented in favour of complicated character of molecular rearrangements in lipid-water phases in the pretransition region and impossibility at present to correlate structural and calorimetric data when estimating premelting phenomena.

Calorimetry↗
PubMed1987

A structural model for the alpha-subunit of transducin. Implications of its role as a molecular switch in the visual signal transduction mechanism.

Transducin is a GTP-binding protein which mediates the light activation signal from photolyzed rhodopsin to cGMP phosphodiesterase and is pivotal in the visual excitation process. Biochemical studies suggest that the T alpha subunit of transducin is composed of three functional domains, one for rhodopsin/T beta gamma interaction, another for guanine nucleotide binding, and a third for the activation of phosphodiesterase. The integration of the primary sequence of T alpha along with secondary structure, hydropathy and folding topology predictions, and a comparison with homologous proteins have led to the construction of a three-dimensional model of the T alpha subunit. A molecular mechanism which underlies the coupling action of T alpha is suggested on the basis of this model.

Enzyme Activation↗
PubMed2003

Implicit solvent model estimates of the stability of model structures of the alamethicin channel.

Alamethicin is a hydrophobic helical peptide of 20 residues, which oligomerizes to form ion-conducting channels in membranes. The behavior of an intact alamethicin channel in POPC bilayers was recently studied, using 2 ns molecular dynamics (MD) simulations of a model hexameric channel. These simulations produced numerous conformations of the channel. In the present study, we used 11 of these channel conformations and carried out continuum-solvent model calculations, similar to those used for the monomers in our previous studies, to investigate the energetics of the channel inside the lipid bilayer. Our results suggest that, out of the 11 channel conformations produced by the MD simulations, only four are stable inside the lipid bilayer, with water-to-membrane free energies of transfer ranging from approximately -6 to approximately -10 kcal/mol. Analysis of the results suggests two causes for the apparent instability of the remainder of the structures inside the lipid bilayer, both resulting from the desolvation of channel polar groups (i.e. their transfer from the aqueous phase into the bilayer). The first is specific, uncompensated backbone hydrogen bonds, which exist in the region of the channel exposed to the hydrocarbon of the lipid bilayer. The second is exposure of intra-pore water molecules to the surrounding lipid. Thus, the association of these structures with the membrane involves a large electrostatic desolvation free-energy penalty. The apparent conflict between continuum-solvent and MD calculations, and its significance for the interpretation of membrane proteins simulations, are discussed.

Alamethicin↗
PubMed2002

A structural model for the high-valent intermediate Q of methane monooxygenase from broken-symmetry density functional and electrostatics calculations.

A combined broken-symmetry density functional and electrostatics approach has been used to construct a model for the high-valent diiron intermediate Q of methane monooxygenase. The presence of high-spin or intermediate spin iron centers gives rise to two structurally distinct spin-coupled states of the cluster for which calculated geometries, net spin populations, Heisenberg J values, Mössbauer isomer shifts, and quadrupole splittings are compared and contrasted with the available spectroscopic data.

Binding Sites↗