Reevaluating equilibrium and kinetic binding parameters for lipophilic drugs based on a structural model for drug interaction with biological membranes.
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Cell Membrane↗
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Envelope structure model of human immunodeficiency virus type 1.
The envelope structure of human immunodeficiency virus type 1 (HIV-1) was examined using a computer image processor combined with an image rotation-averaging system. Our results indicate that the envelope of the HIV-1 particle is constructed of a T-7 laevo icosahedral surface net, and the knobs are distributed in the positions of pentamer-hexamer clustering, the total number being 72, which correspond to the results obtained by Gelderblom et al. and Ozel et al.
HIV-1↗
A structured model for vegetative growth and sporulation in Bacillus thuringiensis.
A mathematical model has been developed for the delta-endotoxin producing Bacillus thuringiensis. The structure of the model involves the processes taking place during vegetative growth, those leading to the initiation of sporulation under conditions of carbon and/or nitrogen limitation, and the sporulation events. The key features in the model are the pools of compounds, such as PRPP, IMP, ADP/ATP, GDP/GTP, pyrimidine nucleotides, NAD/NADH2, amino acids, nucleic acids, cell wall, and vegetative and sporulation proteins. These, along with sigma-factors that control the nature of RNA-polymerase during the different phases, effectively stimulate the vegetative growth and sporulation. The initiation of sporulation is controlled by the intracellular concentration of GTP. Results of simulation of vegetative growth, initiation of sporulation, spore protein formation, and production of delta-endotoxin under C- or N-limitation are presented.
Ammonia↗
A structural model for the kinetic behavior of hemoglobin.
The tertiary structures of all liganded hemoglobins in the R state differ in detail. Steric hindrance arising from nonbonded ligand-globin interactions affects the binding of ligands such as CO and cyanide which preferentially form linear axial complexes to heme; these ligands bind in a strained off-axis configuration. Ligands such as O2 and NO, which preferentially form bent complexes, encounter less steric hindrance and can bind in their (preferred) unstrained configuration. Linear complexes distort the ligand pockets in the R state (and by inference, in the T state) more than bent complexes. These structural differences between linear and bent complexes are reflected in the kinetic behavior of hemoglobin. Structural interpretation of this kinetic behavior indicates that the relative contributions of nonbonded ligand-globin interactions and nonbonded heme interactions to transition state free energies differ for linear and bent ligands. The relative contributions of these interactions to the free energy of cooperativity may also differ for linear and bent ligands. Thus the detailed molecular mechanism by which the affinity of heme is regulated differs for different ligands.
Allosteric Regulation↗
Spectroscopic studies and a structural model for blue copper centers in proteins.
Low temperature absorption, circular dichroism, and magnetic circular dichroism spectral studies of the blue copper proteins Rhus vernicifera stellacyanin, bean plastocyanin, and Pseudomonas aeruginosa azurin have been made. Low energy bands attributable to the d-d transitions 2B2 leads to 2E and 2B2 leads to 2B1 in a flattened tetrahedral (D 2d) copper-(II) center are observed in these proteins at about 5000 and 10,000 cm-1, respectively. The band positions accord well with ligand field calculations based on a tetrahedral structure that is distorted approximately 6 degrees toward a square plane. The ligands in this flattened tetrahedral coordination unit in bean plastocyanin are identified from various spectroscopic experiments as His-38, Cys-85, His-88, and a deprotonated peptide nitrogen (N) a few residues above His-38.
Azurin↗
Activity, disulphide mapping and structural modelling of the fifth domain of human beta 2-glycoprotein I.
Complexes formed by the interaction of negatively charged phospholipids and beta 2-glycoprotein I (beta 2-I) are the target of autoantibodies in systemic lupus erythematosus. The highly positively charged fifth (C-terminal) domain of human beta 2-I was produced as a fusion protein in an Escherichia coli expression system and was shown to bind to the negatively charged phospholipid, cardiolipin, almost as well as the intact protein. In an attempt to define the 3D structure of this domain, the disulphide linkage pattern was determined and shown to be Cys 1-4, Cys 2-5 and Cys 3-6 in contradiction to an earlier report. In the light of this information, the sequence of the fifth domain of beta 2 I (beta 2-I-5) is readily aligned with that of the 16th repeat of factor H, of which the 3D structure is known, and a model of beta 2I-5 has been built by homology. On the basis of the model we suggest residues that might be the target of profitable site-directed mutagenesis in structure-function studies.
Amino Acid Sequence↗
A structural model for human dihydrolipoamide dehydrogenase.
The hypothesis that dihydrolipoamide dehydrogenases (E3s) have tertiary structures very similar to that of human glutathione reductase (GR) was tested in detail by three separate criteria: (1) by analyzing each putative secondary structural element for conservation of appropriate polar/nonpolar regions, (2) by detailed comparison of putative active site residues in E3s with their authentic counterparts in human GR, and (3) by comparison of residues at the putative dimeric interface of the E3s with the authentic residues in GR. All three criteria are satisfied in a convincing way for the 7 E3s that were considered, supporting the conclusion that the structural scaffolding and the overall tertiary structure (which determines the location of functional sites and residues) are remarkably similar for the E3s and for GR. These analyses together with the crystal structures of human erythrocyte GR formed the basis for construction of a molecular model for human E3. The cofactor FAD and the substrates NAD and lipoic acid were also included in the model. Unexpectedly, the surface residues in the cleft that holds the lipoamide were found to be highly charged and predominantly acidic, allowing us to predict that the region around the lipoamide in the subunit should be basic in nature. The molecular model can be tested by site-directed mutagenesis of residues predicted to be in the dihydrolipoamide acetyltransferase subunit binding cleft.
Amino Acid Sequence↗
A structural model for the cholesterol-phosphatidylcholine complexes in bilayer membranes.
Based on the structural properties of phospholipid and cholesterol molecules, and making use of the known structural and motional effects of cholesterol and its analogs on phospholipid bilayers, a model for the cholesterol-phosphatidylcholine complex is proposed. In this model, the 3beta-hydroxyl group of cholesterol is assumed to engage in hydrogen bonding with the carbonyl oxygen of the fatty acyl groups in phospholipids. Some specific configurations of the saturated and unsaturated fatty acyl chains of the phospholipid are suggested to participate in van der Waals attractive interactions with the apha and beta surface of the steroid nucleus.
Binding Sites↗
Cloning and sequence analysis of the 18 S ribosomal RNA gene of tomato and a secondary structure model for the 18 S rRNA of angiosperms.
The gene of a cytoplasmic 18 S ribosomal RNA (18 S rDNA) of the dicotyledonous plant tomato (Lycopersicon esculentum) cv. Rentita has been cloned, and its complete primary structure has been determined. The tomato 18 S rDNA is 1805 bp long with a G + C content of 49.6%. Its sequence exhibits 94%-96% positional identity when it is colinearly aligned with the previously reported sequences of the 17-18 S rDNAs of the dicot soybean and the monocots maize and rice. A model of the secondary structure of the 18 S rRNA of angiosperms is presented and its genera-specific structural features are compared with a current eukaryotic 18 S rRNA consensus model.
Base Sequence↗
Structural model of the nucleotide-binding conserved component of periplasmic permeases.
The amino acid sequences of 17 bacterial membrane proteins that are components of periplasmic permeases and function in the uptake of a variety of small molecules and ions are highly homologous to each other and contain sequence motifs characteristic of nucleotide-binding proteins. These proteins are known to bind ATP and are postulated to be the energy-coupling components of the permeases. Several medically important eukaryotic proteins, including the multidrug-resistance transporters and the protein encoded by the cystic fibrosis gene, are also homologous to this family. By multiple sequence alignment of these 17 proteins, the consensus sequence, secondary structure, and surface exposure were predicted. The secondary structural motifs that are conserved among nucleotide-binding proteins were identified in adenylate kinase, p21ras, and elongation factor Tu by superposition of their known tertiary structures. The equivalent secondary structural elements in the predicted conserved component were located. These, together with sequence information, served as guides for alignment with adenylate kinase. A model for the structure of the ATP-binding domain of the permease proteins is proposed by analogy to the adenylate kinase structure. The characteristics of several permease mutations and biochemical data lend support to the model.
Adenylate Kinase↗
Protein model structure evaluation using the solvation free energy of folding.
A systematic study of solvation free energy of folding for proteins with known crystallographic structures is presented. There is a linear relationship between the solvation free energy of folding and the protein size. This relationship, which can be rationalized by a simple model of chain folding, allows prediction of the solvation free energy of folding for proteins for which no high resolution structures are available. All misfolded structures analyzed show solvation free energies higher than predicted; however, some of the misfolded structures have values close enough to the predicted values so that one must be very careful when using such a criterion to check the correctness of a protein model.
Enzymes↗
Hemoglobin Saint Mandé [beta 102 (G4) Asn----Tyr]. Functional studies and structural modeling reveal an altered T state.
Oxygen equilibrium studies of purified hemoglobin Saint Mandé (Hb SM) [beta 102 (G4) Asn----Tyr] reveal a decreased oxygen affinity and cooperativity but to a lesser extent than found for Hb Kansas (beta 102 Thr). The low affinity of Hb SM depends on environmental conditions: eliminating chloride or raising the pH greatly elevated the ratio of p50 of Hb SM to that of Hb A. The alkaline Bohr effect is reduced by about 40%. The effects of anions (chloride, organophosphates) binding to deoxy Hb SM are also reduced. These data indicate that the functional properties of Hb SM are intermediary between Hb A and Hb Kansas. In addition, molecular graphics modeling of Hb SM in the oxy and deoxy structures indicate the possibility of a new hydrogen bond in the T state between beta(1)102 Tyr and alpha(2)42 Tyr. Stabilisation of the T state in this manner is a plausible explanation for several of the effects observed.
Asparagine↗
Structural modelling of P-type ion pumps.
Over forty sequences of P-type ion pumps have been determined. They fall into five families showing between 20% and 50% identity in sequence. The conserved residues are concentrated in several regions which are found in all the pumps. All the defined functional sites are associated with conserved segments and provide a basis for subdivision into domains, to which tentative secondary and tertiary structures can be assigned. The domains have been assembled into a structure consisting of a conserved core with variable loops and deletions on the surface, which accommodates site mutants, affinity labels and known epitopes. This model has been correlated with the results of an electron crystallographic study of the Ca++ pump. Two types of crystal have been examined in negative stain and in amorphous ice; thin plates which diffract to 4A and long helical tubes which diffract to 15A. The plates have given a 6A projection map, some of which can be interpreted by difference from the map of the negatively stained crystal, as transmembrane helices. Three dimensional interpretation will require a tilt series. In the meantime, analysis of the tubes has given a 14A 3D map which clearly defines the cytoplasmic domains and their relation to the transmembrane region (Stokes and Toyoshima in preparation). Although it is not yet possible to assign specific functions to the cytoplasmic lobes, the structure at this resolution is consistent with the model.
Animals↗
Structural modeling of the distamycin A-d(CGCGAATTCGCG)2 complex using 2D NMR and molecular mechanics.
The structure of the distamycin A-d(CGCGAATTCGCG)2 complex has been determined through a combination of SKEWSKY and NOESY 2D NMR experiments and molecular mechanics calculations. NMR data provided upper bounds on many proton-proton pairs. The advantage of the SKEWSKY/NOESY method is that small groups of strongly coupled spins can be treated accurately as isolated systems. The AMBER molecular mechanics package, modified to include the NMR constraints, was used in energy refinements. Distamycin A fits snugly into the 5'-AATT-3' minor-groove binding site. Structural analysis revealed van der Waals contacts between A5, A6, and A18 C2H and drug H3 protons, potential three-center hydrogen bonding between drug amide protons and adenine N3 and thymine O2 atoms analogous to the spine of hydration in the crystal structure of the free DNA, and stacking of the sugar O1' atoms of A6-C21, T7-T20, and, T8-T19, over drug pyrrole rings 1, 2, and 3, respectively. In addition to hydrophobic effects, hydrogen bonding, and electrostatic interactions proposed by others, it is suggested that stacking interactions between DNA sugar O1' atoms and the three drug pyrrole rings contribute to the stability of the complex.
Base Composition↗
Structural model for T-cell recognition of HLA class II-associated alloepitopes.
In an effort to investigate the structure-function relationship of HLA class II molecules vis-à-vis alloepitope expression, cloned T-cell reagents were used to define polymorphic epitopes associated with DR and DQ molecules. DNA sequences of genes encoding allelic or isotypic DR or DQ molecules that appear to express the same T-cell-defined epitopes were compared in an attempt to identify association of shared sequences with shared epitopes. When sequence sharing is associated with shared epitope expression, we suggest that it is the shared sequence that encodes the epitope in question. Based on the hypothetical three-dimensional structure of the class II molecule, an approximation is made as to which parts of the HLA class II molecule are involved in alloepitope expression. T-cell clones were generated from cells primed against HLA-DR2 haplotypes representing the cellularly defined subgroups Dw2 or Dw21 (previously designated MN2, FJ0, or Tb24). Those clones determined to be DR- or DQ-directed based on monoclonal antibody inhibition assays were tested by panel cell analysis utilizing DR2-positive and DR2-negative target cells. The data support the concept that amino acids 67, 70, 71, and 74 for DR molecules and amino acids 57, 70, and 71 for DQ molecules, which appear to comprise one face of the alpha helix, are of primary importance in T-cell recognition. In other cases, sharing of both the second hypervariable region (amino acids 25-33) and the third hypervariable region (amino acids 67-74) appears necessary to explain epitope sharing for DR molecules. We emphasize that the involvement of these two hypervariable regions may indicate that alloepitope expression involves the complex of class II molecule plus peptide, with the second HVR primarily involved in determining which peptides are bound and the third in T-cell receptor (TcR) recognition and/or peptide binding; we do not rule out that conformational changes of the second HVR can induce conformational changes in the third HVR. Finally, shared alloepitopes detected by some clones could not be explained based on shared primary sequences.
Amino Acid Sequence↗
Comparative analysis of viral cysteine protease structural models.
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Amino Acid Sequence↗
Structural model of vinculin: correlation of amino acid sequence with electron-microscopical shape.
The cytoskeleton-associated protein vinculin exhibits the shape of a 'balloon on a string' when examined by rotary shadowing electron microscopy. Recently, the complete primary structure of chicken vinculin was determined which leads to the questions as to whether the globule might be either hollow or disc shaped, or whether the electron micrographs resemble those of vinculin dimers. Based on a hydrodynamical theory, evidence is presented for the assumption that vinculin as a monomer consists of a compact spherical head 6 nm in diameter connected by a proline-rich domain to a rod-shaped tail about 20 nm in length.
Amino Acid Sequence↗
A structural model for the retroviral proteases.
In many retroviruses the 5' end of the pol gene codes for a protease vital for the processing of the gag polyprotein into the separate core proteins. In some viruses this protease is encoded at the 3' end of the gag gene, or between the gag and pol genes in a different reading frame to either. A sequence, Asp-Thr-Gly, which is conserved in retroviral proteases is also conserved in the active sites of aspartic proteases, an observation which has led to the suggestion that the retroviral proteases could belong to this family. We have examined the sequences of the aspartic and retroviral protease families, using pattern-recognition, structure prediction and molecular modelling techniques, and conclude that the viral protease sequences probably correspond to a single domain of an aspartic protease and may function in a dimeric form. We have constructed a model of the pol-protease of human immunodeficiency virus 1 (HIV-1) to test this hypothesis.
Amino Acid Sequence↗