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PubMed1998

Structural classification of alphabetabeta and betabetaalpha supersecondary structure units in proteins.

We present a fully automatic structural classification of supersecondary structure units, consisting of two hydrogen-bonded beta strands, preceded or followed by an alpha helix. The classification is performed on the spatial arrangement of the secondary structure elements, irrespective of the length and conformation of the intervening loops. The similarity of the arrangements is estimated by a structure alignment procedure that uses as similarity measure the root mean square deviation of superimposed backbone atoms. Applied to a set of 141 well-resolved nonhomologous protein structures, the classification yields 11 families of recurrent arrangements. In addition, fragments that are structurally intermediate between the families are found; they reveal the continuity of the classification. The analysis of the families shows that the alpha helix and beta hairpin axes can adopt virtually all relative orientations, with, however, some preferable orientations; moreover, according to the orientation, preferences in the left/right handedness of the alpha-beta connection are observed. These preferences can be explained by favorable side by side packing of the alpha helix and the beta hairpin, local interactions in the region of the alpha-beta connection or stabilizing environments in the parent protein. Furthermore, fold recognition procedures and structure prediction algorithms coupled to database-derived potentials suggest that the preferable nature of these arrangements does not imply their intrinsic stability. They usually accommodate a large number of sequences, of which only a subset is predicted to stabilize the motif. The motifs predicted as stable could correspond to nuclei formed at the very beginning of the folding process.

Algorithms↗
PubMed1992

Sequence-structure matching in globular proteins: application to supersecondary and tertiary structure determination.

A methodology designed to address the inverse globular protein-folding problem (the identification of which sequences are compatible with a given three-dimensional structure) is described. By using a library of protein finger-prints, defined by the side chain interaction pattern, it is possible to match each structure to its own sequence in an exhaustive data base search. It is shown that this is a permissive requirement for the validation of the methodology. To pass the more rigorous test of identifying proteins that are not close sequence homologs, but that have similar structure, the method has been extended to include insertions and deletions in the sequence, which is compared to the fingerprint. This allows for the identification of sequences having little or no sequence homology to the fingerprint. Examples include plastocyanin/azurin/pseudoazurin, the globin family, different families of proteases and cytochromes, including cytochromes c' and b-562, actinidin/papain, and lysozyme/alpha-lactalbumin. Turning to supersecondary structure prediction, we find that alpha/beta/alpha fragments possess sufficient specificity to identify their own and related sequences. By threading a beta-hairpin through a sequence, it is possible to predict the location of such hairpins and turns with remarkable fidelity. Thus, the method greatly extends existing techniques for the prediction of both global structural homology and local supersecondary structure.

Amino Acid Sequence↗
PubMed1994

Structure from function: screening structural models with functional data.

Structural constraints derived from different antibody epitopes on human growth hormone (hGH) were used to screen three-dimensional models of hGH that were generated by computer algorithms. Previously, alanine-scanning mutagenesis defined the residues that modulate binding to 21 different monoclonal antibodies to hGH. These functional epitopes were composed of 4-14 side chains whose alpha-carbons clustered within 4-23 A. Distance and topographic constraints for these functional epitopes were virtually the same as constraints derived from known x-ray structures of protein-antigen complexes. The constraints were used to evaluate about 1400 models of hGH that were computer-generated by a secondary-structure prediction and packing algorithm. On average each functional epitope reduced the number of models in the pool by a factor of 2, so that 8 monoclonal antibodies could reduce the number of possible models to < 10. The average root-mean-square deviation of alpha-carbon coordinates between the x-ray structure and either the pool of starting models or final models ranged from 13 to 16 A or 4 to 7 A, respectively, depending on the pool of starting models and the level of constraints imposed. All of the final models had the correct folding topography, and the best model was within 3.8 A root-mean-square deviation of the x-ray coordinates. This model was as close as it could have been because the models were built by using ideal helices and those in the x-ray structure are not. Our studies suggest that epitope mapping data can effectively screen structural models and, when coupled to predictive algorithms, can help to generate low-resolution models of a protein.

Amino Acid Sequence↗
PubMed2005

Structural mechanism governing the quaternary organization of monocot mannose-binding lectin revealed by the novel monomeric structure of an orchid lectin.

Two isoforms of an antifungal protein, gastrodianin, were isolated from two subspecies of the orchid Gastrodia elata, belonging to the protein superfamily of monocot mannose-specific lectins. In the context that all available structures in this superfamily are oligomers so far, the crystal structures of the orchid lectins, both at 2.0 A, revealed a novel monomeric structure. It resulted from the rearrangement of the C-terminal peptide inclusive of the 12th beta-strand, which changes from the "C-terminal exchange" into a "C-terminal self-assembly" mode. Thus, the overall tertiary scaffold is stabilized with an intramolecular beta-sheet instead of the hybrid observed on subunit/subunit interface in all known homologous dimeric or tetrameric lectins. In contrast to the constrained extended conformation with a cis peptide bond between residues 98 and 99 commonly occurring in oligomers, a beta-hairpin forms from position 97 to 101 with a normal trans peptide bond at the corresponding site in gastrodianin, which determines the topology of the C-terminal peptide and thereby its unique fold pattern. Sequence and structure comparison shows that residue replacement and insertion at the position where the beta-hairpin occurs in association with cis-trans inter-conversion of the specific peptide bond (97-98) are possibly responsible for such a radical structure switch between monomers and oligomers. Moreover, this seems to be a common melody controlling the quaternary states among bulb lectins through studies on sequence alignment. The observations revealed a structural mechanism by which the quaternary organization of monocot mannose binding lectins could be governed. The mutation experiment performed on maltose-binding protein-gastrodianin fusion protein followed by a few biochemical detections provides direct evidence to support this conclusion. Potential carbohydrate recognition sites and biological implications of the orchid lectin based on its monomeric state are also discussed in this paper.

Amino Acid Sequence↗
PubMed2006

Unexpected structural diversity in alkali metal azide-crown ether complexes: syntheses, X-ray structures, and quantum-chemical calculations.

A series of alkali metal azide-crown ether complexes, [Li([12]crown-4)(N3)], [Na([15]crown-5)(N3)], [Na([15]crown-5)(H2O)2]N3, [K([18]crown-6)(N3)(H2O)], [Rb([18]crown-6)(N3)(H2O)], [Cs([18]crown-6)(N3)]2, and [Cs([18]crown-6)(N3)(H2O)(MeOH)], has been synthesised. In most cases, single crystals were obtained, which allowed X-ray crystal structures to be derived. The structures obtained have been compared with molecular structures computed by density functional theory (DFT) calculations. This has allowed the effects of the crystal lattice on the structures to be investigated. Also, a study of the M-N(terminal) metal-azide bond length and charge densities on the metal (M) and terminal nitrogen centre (N(terminal)) in these complexes has allowed the nature of the metal-azide bond to be probed in each case. The bonding in these complexes is believed to be predominantly ionic or ion-dipole in character, with the differences in geometries reflecting the balance between maximising the coordination number of the metal centre and minimising ligand-ligand repulsions. The structures of the crown ether complexes determined in this work show the subtle interplay of such factors. The significant role of hydrogen bonding is also demonstrated, most clearly in the structures of the K and Rb dimers, but also in the chain structure of the hydrated Cs complex.

Journal Article↗
PubMed2002

Automated docking to multiple target structures: incorporation of protein mobility and structural water heterogeneity in AutoDock.

Protein motion and heterogeneity of structural waters are approximated in ligand-docking simulations, using an ensemble of protein structures. Four methods of combining multiple target structures within a single grid-based lookup table of interaction energies are tested. The method is evaluated using complexes of 21 peptidomimetic inhibitors with human immunodeficiency virus type 1 (HIV-1) protease. Several of these structures show motion of an arginine residue, which is essential for binding of large inhibitors. A structural water is also present in 20 of the structures, but it must be absent in the remaining one for proper binding. Mean and minimum methods perform poorly, but two weighted average methods permit consistent and accurate ligand docking, using a single grid representation of the target protein structures.

Computer Simulation↗
PubMed1992

Variability of conformations at crystal contacts in BPTI represent true low-energy structures: correspondence among lattice packing and molecular dynamics structures.

The structures of five basic pancreatic trypsin inhibitor (BPTI) molecules are compared to establish the extent and nature of the conformational variability resulting from crystal packing effects. BPTI is an ideal system to evaluate such factors because of the availability of high resolution X-ray models of five different BPTI structures, each in a different crystal packing environment. Differences observed among the structures are found to be distributed throughout the molecule, although the regions that display most variability are associated with the loop structures (residues 14-17 and 24-29). The regions of structure that show the largest rms deviations from the mean of the five packing motifs correlate well with the presence of intermolecular contacts in the crystal lattice. For most of the molecules there is also a correspondence between a larger number of intermolecular contacts and systematically higher B-factors, although it is not apparent whether this is induced by the crystal contact or results from the fact that the contacts are made predominantly through surface loops. The conformational differences seen among the X-ray models constitute more than local shifts at the lattice contact surfaces, and in fact involve in some cases the making and breaking of intramolecular H-bonds. The magnitudes of the differences among packing models are significantly larger than those usually associated with changes induced by mutagenesis; for instance; the structural differences at the site of mutation observed on removing an internal disulfide from the molecule are significantly less than those associated with lattice contact effects. The crystal packing conformations are compared to representative structures of BPTI generated during a 96-psec molecular dynamics (MD) simulation. This comparison shows a high level of correspondence between the protein flexibility indicated by the X-ray and MD analyses, and specifically between those regions that are most variable. This suggests that the regions that show most variability among the crystal packing models are not artifacts of crystallization, but rather represent true low-energy conformers that have been preferentially selected by crystallization factors.

Amino Acid Sequence↗
PubMed1995

SCOP: a structural classification of proteins database for the investigation of sequences and structures.

To facilitate understanding of, and access to, the information available for protein structures, we have constructed the Structural Classification of Proteins (scop) database. This database provides a detailed and comprehensive description of the structural and evolutionary relationships of the proteins of known structure. It also provides for each entry links to co-ordinates, images of the structure, interactive viewers, sequence data and literature references. Two search facilities are available. The homology search permits users to enter a sequence and obtain a list of any structures to which it has significant levels of sequence similarity. The key word search finds, for a word entered by the user, matches from both the text of the scop database and the headers of Brookhaven Protein Databank structure files. The database is freely accessible on World Wide Web (WWW) with an entry point to URL http: parallel scop.mrc-lmb.cam.ac.uk magnitude of scop.

Amino Acid Sequence↗
PubMed1995

The secondary structure of the adenovirus-2 L4 polyadenylation domain: evidence for a hairpin structure exposing the AAUAAA signal in its loop.

The secondary structure of the adenovirus-2 L4 polyadenylation domain was established using enzymatic attacks and chemical modifications. This domain is characterized by the co-existence of several variants including stem-loop structures of low stability such that its secondary structure is clearly distinct from that of the upstream sequence which harbors large stable hairpin structures. The L4 polyadenylation site is located in a free single-stranded region and the AAUAAA signal is exposed in the 14 nucleotide loop of a hairpin structure with a six-base-pair stem. The 5' arm of this stem includes six nucleotides of a previously identified upstream efficiency element (USEa), whose deletion or substitution reduces cleavage-polyadenylation efficiency by 50%. Several evidences suggest that a signal hairpin structure may be important for polyadenylation. First, the AAUAAA signal is well exposed to enzymes and reagents in its two co-existing variants, suggesting that it is also accessible to cleavage-polyadenylation factors. Second, the disruption of the stem induces a 50% decrease of cleavage efficiency in vitro. Third, the reduction of the size of the loop to five nucleotides reduces cleavage efficiency by 90%. Fourth, polyadenylation domains of other origins can be folded into hairpin structures harboring the AAUAAA signal in their loop. We propose that one of the functions of an upstream efficiency element could be to participate in the presentation of the signal to trans-acting factors.

Adenovirus E3 Proteins↗
PubMed1995

Structural studies on corn nitrate reductase: refined structure of the cytochrome b reductase fragment at 2.5 A, its ADP complex and an active-site mutant and modeling of the cytochrome b domain.

The refined crystal structures of the recombinant cytochrome b reductase fragment of corn (Zea mays) nitrate reductase, its ADP complex and the active-site mutant Cys242Ser are reported here. The native structure has been refined at 2.5 A resolution to a crystallographic R-factor of 18.7% with root-mean-square (r.m.s) deviations from standard bond lengths and angles of 0.013 A and 2.0 degrees. The diffraction pattern of the crystals is highly anisotropic and correction of this effect lowered the crystallographic R-factor by 5% during the refinement. The structure of the enzyme co-crystallized with ADP has been solved at 2.7 A resolution and refined to an R-factor of 18.6% with r.m.s. deviations from standard bond lengths and angles of 0.014 A and 2.1 degrees. It revealed the binding site of the ADP moiety of the NADH cofactor, which is the electron donor for nitrate reduction. Based on this structure, a model of NADH at the active site of the enzyme was built and the implications for electron transfer from NADH to the flavin cofactor are discussed. The crystal structure of an active-site mutant enzyme, Cys242Ser, has been solved by difference Fourier synthesis and refined to an R-factor of 19.0% to 3.0 A resolution with standard deviations of bond lengths and angles of 0.017 A and 2.5 degrees. This structure analysis suggests that the observed decrease in catalytic activity of this mutant might be due to misalignment of the nicotinamide ring in its binding site. A model of the heme-containing domain of nitrate reductase has been built based on the X-ray structure of bovine cytochrome b5 and has been docked with the cytochrome b reductase fragment of nitrate reductase. The model of the complex contains six salt-bridges at the domain-domain interface and a hydrophobic core. In this model, His48, an invariant residue in the cytochrome b reductase family, forms an interaction with the propionic acid group of the D-ring of the heme cofactor. This group is in contact with the C-8 methyl group of the flavin ring. Residues that might influence the redox potential of the flavin cofactor are proposed and their possible role in electron transfer is discussed.

Adenosine Diphosphate↗
PubMed1995

High resolution crystal structures of amphibian red-cell L ferritin: potential roles for structural plasticity and solvation in function.

Ferritin is a highly conserved multisubunit protein in animals, plants and microbes which assembles with cubic symmetry and transports hydrated iron ions and protons to and from a mineralized core in the protein interior. We report here the high resolution structures of recombinant amphibian red-cell L ferritin and two mutants solved under two sets of conditions. In one mutant, Glu56, 57, 58 and 60 were replaced with Ala, producing a lag phase in the kinetics of iron uptake. In the second mutant, His25 was replaced with Tyr with, at most, subtle effects on function. A molecule of betaine, used in the purification, is bound in all structures at the 2-fold axis near the recently identified heme binding site of bacterioferritin and horse spleen L ferritin. Comparisons of the five amphibian structures identify two regions of the molecule in which conformational flexibility may be related to function. The positions and interactions of a set of 10 to 18 side-chains, most of which are on the inner surface of the protein, are sensitive both to solution conditions and to the Glu-->Ala mutation. A subset of these side-chains and a chain of ordered solvent molecules extends from the vicinity of Glu56 to 58 and Glu60 to the 3-fold channel in the wild type protein and may be involved in the transport of either iron or protons. The "spine of hydration" is disrupted in the Glu-->Ala mutant. In contrast, H25Y mutation shifts the positions of backbone atoms between the site of the mutation and the 4-fold axis and side-chain positions throughout the structure; the largest changes in the position of backbone atoms are in the DE loop and E helix, approximately 10 A from the mutation site. In combination, these results indicate that solvation, structural plasticity and cooperative structural changes may play a role in ferritin function. Analogies with the structure and function of ion channel proteins such as annexins are noted.

Amphibians↗
PubMed1999

Structural flexibility in human topoisomerase I revealed in multiple non-isomorphous crystal structures.

Human topoisomerase I plays a critical role in chromosomal stability by relaxing the DNA superhelical tension that arises from a variety of nuclear processes, including replication, transcription, and chromatin remodeling. Human topoisomerase I is a approximately 91 kDa enzyme composed of four major domains: a 24 kDa N-terminal domain, a56 kDa core domain, a7 kDa linker domain, and a6 kDa C-terminal domain containing the active-site Tyr723 residue. A monoclinic crystal structure of a 70 kDa N-terminally truncated form of human topoisomerase I in non-covalent complex with a 22 bp DNA duplex exhibited remarkable crystal-to-crystal non-isomorphism; shifts in cell constants of up to 9 A in the b -axis length and up to 8.5 degrees in the beta-angle were observed. Eight crystal structures of human topoisomerase I - DNA complexes from this crystal form were determined to between 2.8 and 3.25 A resolution. These structures revealed both dramatic shifts in crystal packing and functionally suggestive regions of conformational flexibility in the structure of the enzyme. Crystal packing shifts of up to 20.5 A combined with rotations of up to 11.5 degrees were observed, helping to explain the variability in cell constants. When the core subdomain III regions of the eight structures are superimposed, the "cap" (core subdomains I and II) of the molecule is observed to rotate by up to 4.6 degrees and to shift by up to 3.6 A. The linker domain shows the greatest degree of conformational flexibility, rotating and shifting by up to 2.5 degrees and 4.6 A, respectively, in five of eight structures, and becoming disordered altogether in the remaining three. These observed regions of conformational flexibility in the cap and the linker domain are consistent with the structural flexibility invoked in the "controled rotation" mechanism proposed for the relaxation of DNA superhelical tension by human topoisomerase I.

Crystallization↗
PubMed2000

Searching the protein structure databank with weak sequence patterns and structural constraints.

A method is described in which proteins that match PROSITE patterns are filtered by the root-mean-square deviation of the local 3D structures of the probe and target over the pattern components. This was found to increase the discrimination between true and false members of the protein family but was dependent on how unique the structural features in the pattern were compared to equivalent fragments extracted from the structure databank (for example; if the pattern fell in an alpha-helix, then discrimination was poor.) We then generalised the sequence patterns (by widening the range of amino acid residues allowed at each position) and monitored how well the structural information helped retain specificity. While the discrimination of the pure sequence pattern had generally disappeared at information content values less than ten bits, the discrimination of the combined sequence structure probe remained high at this point before following a similar decay. The displacement between these curves indicates that the structural component is, on average, equivalent to about ten bits. The sequence patterns were also filtered using the structure comparison program SAP, giving a global, rather than local "view" of the proteins. This allowed the information content of the sequence patterns to become even less specific but raised problems of whether some proteins encountered with the same fold but no PROSITE pattern should constitute family members.

Amino Acid Motifs↗
PubMed1984

Partitioning of paracellular conductance along the ileal crypt-villus axis: a hypothesis based on structural analysis with detailed consideration of tight junction structure-function relationships.

Current models of intestinal transport suggest cells which absorb ions are located on the villus while secretory cells are located in the crypt and putatively have paracellular pathways which are highly conductive to Na+. One approach to assess possible variation in small intestinal paracellular conductance along the crypt-villus axis is to morphometrically analyze the structural aspects of crypt and villus tight junctions (TJs) which relate to paracellular resistance. Such detailed analysis of junctional structure in this heterogeneous epithelium would permit one to compare intestinal TJ structure-function relationships with those in a structurally simpler epithelium such as that of toad urinary bladder. This comparison would also be of considerable interest since previous similar comparisons have failed to consider in detail the geometric dissimilarity between these two epithelia. We applied light, electron microscopic, and freeze-fracture morphometric techniques to guinea pig ileal mucosa to quantitatively assess, for both crypts and villi, linear TJ density, relative surface contributions, and TJ strand counts. Mean linear TJ densities were 76.8 m/cm2 for crypt cells and 21.8 m/cm2 for villus absorptive cells. Mean TJ strand counts were 4.45 for undifferentiated crypt cell TJs and 6.03 for villus absorptive cell TJs. The villus constituted 87% and the crypt 13% of total surface. We utilized these data to predict paracellular conductance of crypts vs. villi based on equations derived from those of Claude (P. Claude, J. Membrane Biol. 39:219-232, 1978). Such analysis predicts that 73% of ileal paracellular conductance is attributable to the crypt. Furthermore, we obtained literature values for paracellular resistance in mammalian ileum and toad urinary bladder and for toad bladder TJ structure and linear density and constructed a relationship which would allow us to more accurately compare TJ structure-function correlates between these two epithelia. Such a comparison, which considers both surface amplification and TJ structure and distribution in these epithelia, shows that one would predict in vitro measured values for paracellular resistance should be approximately two orders of magnitude less in mammalian ileum than in toad urinary bladder. This predicted discrepancy (115-fold) correlates well with the observed difference (100-fold).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2001

The crystal structures of Phascolopsis gouldii wild type and L98Y methemerythrins: structural and functional alterations of the O2 binding pocket.

Reported are the X-ray crystal structures of recombinant Phascolopsis gouldii methemerythrin (1.8-A resolution) and the structure of an O2-binding-pocket mutant, L98Y methemerythrin (2.1-A resolution). The L98Y hemerythrin (Hr) has a greatly enhanced O2 affinity, a slower O2 dissociation rate, a larger solvent deuterium isotope effect on this rate, and a greater resistance to autoxidation relative to the wild-type protein. The crystal structures show that the hydrophobic binding pocket of Hr can accommodate substitution of a leucyl by a tyrosyl side chain with relatively minor structural rearrangements. UV/vis and resonance Raman spectra show that in solution L98Y methemerythrin contains a mixture of two diiron site structures differing by the absence or presence of an Fe(III)-coordinated phenolate. However, in the crystal, only one L98Y diiron site structure is seen, in which the Y98 hydroxyl is not a ligand, but instead forms a hydrogen bond to a terminal hydroxo/aqua ligand to the nearest iron. Based on this crystal structure, we propose that in the oxy form of L98Y hemerythrin the non-polar nature of the binding pocket favors localization of the Y98 hydroxyl near the O2 binding site, where it can donate a hydrogen bond to the hydroperoxo ligand. The stabilizing Y98OH-O2H-interaction would account for all of the altered O2 binding properties of L98Y Hr listed above.

Animals↗
PubMed2000

Glomerular structural changes and structural-functional relationships at early stage of diabetic nephropathy in Japanese type 2 diabetic patients.

Details of renal structural changes and structural-functional relationships at the early stage of diabetic nephropathy (DN) in type 2 diabetes are not well known. The present review focuses on these topics from previous studies using light and electron microscopic morphometric analysis. Glomerular hypertrophy, one of the histological changes in DN, is present in type 2 as well as in type 1 diabetic patients. However, mechanisms of increased glomerular size might be different from those in type 1 diabetes. Other typical glomerular changes, glomerular basement membrane thickening and mesangial expansion, are present in normoalbuminuric type 2 diabetic patients as a group. However, these parameters are similar between normo- and microalbuminuric patients. Renal structural-functional relationships cannot be seen in type 2 diabetic patients and therefore urinary albumin might not be a reliable indicator for glomerular structural changes in type 2 diabetic patients. Although previous reports showed reversibility of advanced diabetic glomerulosclerosis in type 1 diabetes by 10 years of strict glycemic control, there is no report regarding histological reversibility by therapeutic interventions in type 2 diabetic patients. In addition, it is unclear whether DN lesions are concordant or discordant with diabetic retinopathy grade in type 2 diabetes. From this information, renal structural changes or structural-functional relationships in type 2 diabetic patients might be heterogeneous and different from those in type 1 diabetic patients. Careful longitudinal study of renal structure and function including serial renal biopsy at the early stage of DN in type 2 diabetes is necessary.

Diabetes Mellitus, Type 2↗
PubMed1996

MS-271, a novel inhibitor of calmodulin-activated myosin light chain kinase from Streptomyces sp.--II. Solution structure of MS-271: characteristic features of the "lasso' structure.

MS-271 is a potent inhibitor of smooth muscle myosin light chain kinase (MLCK), obtained from Streptomyces sp. In the previous paper, we reported on the isolation, structural determination and biological properties of MS-271.(1) In this paper, we report on the three-dimensional structure of MS-271 determined by 1H NMR in deuterated dimethyl sulphoxide. MS-271 consists of 21 amino acid residues with a novel internal linkage between the beta-carboxyl group of Asp9 and the alpha-amino group of Cysl, and two disulfide bonds, Cys1-Cys13 and Cys7-Cys19. The internal linkage between the side chain of Asp9 and the alpha-amino group of the N-terminal residue is the same as that of the endothelin B receptor selective antagonist, RES-701-1, that we previously reported. The structural calculations involved the combined use of distance geometry and simulated annealing calculations. The results indicated that MS-271 undergoes extraordinary folding, i.e. the "tail' (Phe10-dTrp21) passes through the "ring' region (Cys1-Asp9) ("lasso' structure). This folding of MS-271 turned out to be the same as the "lasso' structure of RES-701-1. The features of this "lasso' structure are discussed on the basis of comparison between the structures of MS-271 and RES-701-1.

Amino Acid Sequence↗
PubMed2006

Focusing in on structural genomics: the University of Queensland structural biology pipeline.

The flood of new genomic sequence information together with technological innovations in protein structure determination have led to worldwide structural genomics (SG) initiatives. The goals of SG initiatives are to accelerate the process of protein structure determination, to fill in protein fold space and to provide information about the function of uncharacterized proteins. In the long-term, these outcomes are likely to impact on medical biotechnology and drug discovery, leading to a better understanding of disease as well as the development of new therapeutics. Here we describe the high throughput pipeline established at the University of Queensland in Australia. In this focused pipeline, the targets for structure determination are proteins that are expressed in mouse macrophage cells and that are inferred to have a role in innate immunity. The aim is to characterize the molecular structure and the biochemical and cellular function of these targets by using a parallel processing pipeline. The pipeline is designed to work with tens to hundreds of target gene products and comprises target selection, cloning, expression, purification, crystallization and structure determination. The structures from this pipeline will provide insights into the function of previously uncharacterized macrophage proteins and could lead to the validation of new drug targets for chronic obstructive pulmonary disease and arthritis.

Animals↗