Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new computer program to annotate DNA and RNA three-dimensional structures, MC-Annotate, is introduced. The goals of annotation are to efficiently extract and manipulate structural information, to simplify further structural analyses and searches, and to objectively represent structural knowledge. The input of MC-Annotate is a PDB formatted DNA or RNA three-dimensional structure. The output of MC-Annotate is composed of a structural graph that contains the annotations, and a series of HTML documents, one for each nucleotide conformation and base-base interaction present in the input structure. The atomic coordinates of all nucleotides and the homogeneous transformation matrices of all base-base interactions are stored in the structural graph. Symbolic classifications of nucleotide conformations, using sugar puckering modes and nitrogen base orientations around the glycosyl bond, and base-base interactions, using stacking and hydrogen bonding information, are introduced. Peculiarity factors of nucleotide conformations and base-base interactions are defined to indicate their marginalities with all other examples. The peculiarity factors allow us to identify irregular regions and possible stereochemical errors in 3-D structures without interactive visualization. The annotations attached to each nucleotide conformation include its class, its torsion angles, a distribution of the root-mean-square deviations with examples of the same class, the list of examples of the same class, and its peculiarity value. The annotations attached to each base-base interaction include its class, a distribution of distances with examples of the same class, the list of examples of the same class, and its peculiarity value. The distance between two homogeneous transformation matrices is evaluated using a new metric that distinguishes between the rotation and the translation of a transformation matrix in the context of nitrogen bases. MC-Annotate was used to build databases of nucleotide conformations and base-base interactions. It was applied to the ribosomal RNA fragment that binds to protein L11, which annotations revealed peculiar nucleotide conformations and base-base interactions in the regions where the RNA contacts the protein. The question of whether the current database of RNA three-dimensional structures is complete is addressed.
J Mol Biol 2001 May 18
PMID:Quantitative analysis of nucleic acid three-dimensional structures. 1135 82

A common residue numbering scheme for all immunoglobulin variable domains (immunoglobulin light chain lambda (V(lambda)) and kappa (V(kappa)) variable domains, heavy chain variable domains (V(H)) and T-cell receptor alpha (V(alpha)), beta (V(beta)), gamma (V(gamma)) and delta (V(delta)) variable domains) has been devised. Based on the spatial alignment of known three-dimensional structures of immunoglobulin domains, it places the alignment gaps in a way that minimizes the average deviation from the averaged structure of the aligned domains. This residue numbering scheme was applied to the immunoglobulin variable domain structures in the PDB database to automate the extraction of information on structural variations in homologous positions of the different molecules. A number of methods are presented that allow the automated projection of information derived from individual structures or from the comparison of multi-structure alignments onto a graphical representation of the sequence alignment.
J Mol Biol 2001 Jun 08
PMID:Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool. 1139 87

This study reveals that AA and AG oppositions occur frequently at the ends of helices in RNA crystal and NMR structures in the PDB database and in the 16 S and 23 S rRNA comparative structure models, with the G usually 3' to the helix for the AG oppositions. In addition, these oppositions are frequently base-paired and usually in the sheared conformation, although other conformations are present in NMR and crystal structures. These A:A and A:G base-pairs are present in a variety of structural environments, including GNRA tetraloops, E and E-like loops, interfaced between two helices that are coaxially stacked, tandem G:A base-pairs, U-turns, and adenosine platforms. Finally, given structural studies that reveal conformational rearrangements occurring in regions of the RNA with AA and AG oppositions at the ends of helices, we suggest that these conformationally unique helix extensions might be associated with functionally important structural rearrangements.
J Mol Biol 2001 Jul 20
PMID:AA.AG@helix.ends: A:A and A:G base-pairs at the ends of 16 S and 23 S rRNA helices. 1145 84

A homology model of the dopamine D2 receptor was constructed based on the crystal structure of rhodopsin. A putative sodium-binding pocket identified in an earlier model (PDB ) was revised. It is now defined by Asn-419 backbone oxygen at the apex of a pyramid and Asp-80, Ser-121, Asn-419, and Ser-420 at each vertex of the planar base. Asn-423 stabilizes this pocket through hydrogen bonds to two of these residues. Highly conserved Asn-52 is positioned near the sodium pocket, where it hydrogen-bonds with Asp-80 and the backbone carbonyl of Ser-420. Mutation of three of these residues, Asn-52 in helix 1, Ser-121 in helix 3, and Ser-420 in helix 7, profoundly altered the properties of the receptor. Mutants in which Asn-52 was replaced with Ala or Leu or Ser-121 was replaced with Leu exhibited no detectable binding of radioligands, although receptor immunoreactivity in the membrane was similar to that in cells expressing the wild-type D2L receptor. A mutant in which Asn-52 was replaced with Gln, preserving hydrogen-bonding capability, was similar to D2L in affinity for ligands and ability to inhibit cAMP accumulation. Mutants in which either Ser-121 or Ser-420 was replaced with Ala or Asn had decreased affinity for agonists (Ser-121), but increased affinity for the antagonists haloperidol and clozapine. Interestingly, the affinity of these Ser-121 and Ser-420 mutants for substituted benzamide antagonists showed little or no dependence on sodium, consistent with our hypothesis that Ser-121 and Ser-420 contribute to the formation of a sodium-binding pocket.
Mol Pharmacol 2001 Aug
PMID:Modeling and mutational analysis of a putative sodium-binding pocket on the dopamine D2 receptor. 1145 25

Until recently, drawing general conclusions about RNA recognition by proteins has been hindered by the paucity of high-resolution structures. We have analyzed 45 PDB entries of protein-RNA complexes to explore the underlying chemical principles governing both specific and non-sequence specific binding. To facilitate the analysis, we have constructed a database of interactions using ENTANGLE, a JAVA-based program that uses available structural models in their PDB format and searches for appropriate hydrogen bonding, stacking, electrostatic, hydrophobic and van der Waals interactions. The resulting database of interactions reveals correlations that suggest the basis for the discrimination of RNA from DNA and for base-specific recognition. The data illustrate both major and minor interaction strategies employed by families of proteins such as tRNA synthetases, ribosomal proteins, or RNA recognition motifs with their RNA targets. Perhaps most surprisingly, specific RNA recognition appears to be mediated largely by interactions of amide and carbonyl groups in the protein backbone with the edge of the RNA base. In cases where a base accepts a proton, the dominant amino acid donor is arginine, whereas in cases where the base donates a proton, the predominant acceptor is the backbone carbonyl group, not a side-chain group. This is in marked contrast to DNA-protein interactions, which are governed predominantly by amino acid side-chain interactions with functional groups that are presented in the accessible major groove. RNA recognition often proceeds through loops, bulges, kinks and other irregular structures that permit use of all the RNA functional groups and this is seen throughout the protein-RNA interaction database.
J Mol Biol 2001 Aug 03
PMID:Structure-based analysis of protein-RNA interactions using the program ENTANGLE. 1146 58

SuperStar is an empirical method for identifying interaction sites in proteins, based entirely on the experimental information about non-bonded interactions, present in the IsoStar database. The interaction information in IsoStar is contained in scatterplots, which show the distribution of a chosen probe around structure fragments. SuperStar breaks a template molecule (e.g. a protein binding site) into structural fragments which correspond to those in the scatterplots. The scatterplots are then superimposed on the corresponding parts of the template and converted into a composite propensity map. The original version of SuperStar was based entirely on scatterplots from the CSD. Here, scatterplots based on protein-ligand interactions are implemented in SuperStar, and validated on a test set of 122 X-ray structures of protein-ligand complexes. In this validation, propensity maps are compared with the experimentally observed positions of ligand atoms of comparable types. Although non-bonded interaction geometries in small molecule structures are similar to those found in protein-ligand complexes, their relative frequencies of occurrence are different. Polar interactions are more common in the first class of structures, while interactions between hydrophobic groups are more common in protein crystals. In general, PDB and CSD-based SuperStar maps appear equally successful in the prediction of protein-ligand interactions. PDB-based maps are more suitable to identify hydrophobic pockets, and inherently take into account the experimental uncertainties of protein atomic positions. If the protonation state of a histidine, aspartate or glutamate protein side-chain is known, specific CSD-based maps for that protonation state are preferred over PDB-based maps which represent an ensemble of protonation states.
J Mol Biol 2001 Sep 07
PMID:SuperStar: comparison of CSD and PDB-based interaction fields as a basis for the prediction of protein-ligand interactions. 1154 2

During the HIV-1 replication process, interactions between the RNA sequence, named TAR RNA, and the viral protein, Tat, permit a fast and efficient transcription of viral DNA into RNA. Based on the NMR structure of TAR RNA from the PDB, two Peptidic Nucleic Analog- (PNA) based molecules were designed by molecular modelling, the first one targeting G32 U31 and the second targeting U31 C30 free loop bases. Before designing the molecules, the flexibility of the TAR RNA was evaluated by molecular dynamics (MD). The molecules studied are composed of three domains: an arginine, a linker, and two PNA bases. First, molecules were designed and the linker length was optimized to fit the TAR RNA; second, a MD simulation on the TAR RNA molecule complex was performed to validate the molecular structure. Optimal molecules were synthesized and tested on infected cells. The experimental results support the choices made in the design of the molecules.
J Mol Graph Model 2001
PMID:Interaction of new PNA-based molecules with TAR RNA of HIV-1: molecular modelling and biological evaluation. 1155 87

The active site of glucosamine-6-phosphate deaminase from Escherichia coli (GlcN6P deaminase, EC 3.5.99.6) has a complex lid formed by two antiparallel beta-strands connected by a helix-loop segment (158-187). This motif contains Arg172, which is a residue involved in binding the substrate in the active-site, and three residues that are part of the allosteric site, Arg158, Lys160 and Thr161. This dual binding role of the motif forming the lid suggests that it plays a key role in the functional coupling between active and allosteric sites. Previous crystallographic work showed that the temperature coefficients of the active-site lid are very large when the enzyme is in its T allosteric state. These coefficients decrease in the R state, thus suggesting that this motif changes its conformational flexibility as a consequence of the allosteric transition. In order to explore the possible connection between the conformational flexibility of the lid and the function of the deaminase, we constructed the site-directed mutant Phe174-Ala. Phe174 is located at the C-end of the lid helix and its side-chain establishes hydrophobic interactions with the remainder of the enzyme. The crystallographic structure of the T state of Phe174-Ala deaminase, determined at 2.02 A resolution, shows no density for the segment 162-181, which is part of the active-site lid (PDB 1JT9). This mutant form of the enzyme is essentially inactive in the absence of the allosteric activator, N-acetylglucosamine-6-P although it recovers its activity up to the wild-type level in the presence of this ligand. Spectrometric and binding studies show that inactivity is due to the inability of the active-site to bind ligands when the allosteric site is empty. These data indicate that the conformational flexibility of the active-site lid critically alters the binding properties of the active site, and that the occupation of the allosteric site restores the lid conformational flexibility to a functional state.
J Mol Biol 2002 May 24
PMID:On the role of the conformational flexibility of the active-site lid on the allosteric kinetics of glucosamine-6-phosphate deaminase. 1205 45

The design of large macromolecular assemblies is an endeavor with implications for protein engineering as well as nanotechnology. A hierarchic approach was used to design an antiparallel hexameric, tubular assembly of helices. In previous studies, a domain-swapped, dimeric three-helix bundle was designed from first principles. In the crystal lattice, three dimers associate around a 3-fold rotational axis to form a hexameric assembly. Although this hexameric assembly was not observed in solution, it was possible to stabilize its formation by changing three polar residues per monomer to hydrophobic (two Phe and one Trp) residues. Molecular models based on the crystallographic coordinates of DSD (PDB accession code 1G6U) show that these side-chains pack in the central cavity (the "supercore") of the hexameric bundle. Analytical ultracentrifugation, fluorescence spectroscopy, CD spectroscopy, and guanidine-HCl denaturation were used to determine the assembly of the hexamer. To probe the requirements for stabilizing the hexamer, we systematically varied the polarity and steric bulk of one of the Phe residues in the supercore of the hexamer. Depending on the nature of this side-chain, it is possible to modulate the stability of the hexamer in a predictable manner. This family of hexameric proteins may provide a useful framework for the construction of proteins that change their oligomeric states in response to binding of small molecules.
J Mol Biol 2002 May 24
PMID:A hierarchic approach to the design of hexameric helical barrels. 1205 49

Over the last decade, structural biologists have unravelled many proteins that appear natively disordered. Common assumptions are that many of these proteins adopt structure through binding and that the structural flexibility enables them to adopt different functions. Here, we investigated regions of more than 70 sequence-consecutive residues that have no regular secondary structure (NORS). Analysing 31 entirely sequenced organisms, we predicted five times as many proteins with NORS regions (loopy proteins) in eukaryotes (20%) than in prokaryotes and archaeas (4%). Thousands of these NORS regions were over 150 residues long. The amino acid composition of NORS regions differed from that of loops in PDB. Although NORS proteins had significantly more residues in low-complexity regions than other proteins, simple cut-off thresholds for sequence bias missed most NORS regions. On average, NORS regions were evolutionarily at least as conserved as their flanking regions. Furthermore, yeast proteins with NORS regions had more protein-protein interaction partners than other proteins. Regulatory and transcription-related functions were over-represented in loopy proteins, biosynthesis and energy metabolism were under-represented. Overall, our analysis confirmed that proteins with non-regular structures appear to play important functional roles, and they may adopt as yet unknown types of protein structures.
J Mol Biol 2002 Sep 06
PMID:Loopy proteins appear conserved in evolution. 1221 14


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>