ABSTRACT The RCSB Protein Data Bank (RCSB PDB) web site (http://www.pdb.org) has been redesigned to increase usability and to cater to a larger and more diverse user base. This article describes key enhancements and new features that fall into the following categories: (i) query and analysis tools for chemical structure searching, query refinement, tabulation and export of query results; (ii) web site customization and new structure alerts; (iii) pair-wise and representative protein structure alignments; (iv) visualization of large assemblies; (v) integration of structural data with the open access literature and binding affinity data; and (vi) web services and web widgets to facilitate integration of PDB data and tools with other resources. These improvements enable a range of new possibilities to analyze and understand structure data. The next generation of the RCSB PDB web site, as described here, provides a rich resource for research and education.

We present ‘dcGO ’

The current 18th Database Issue of Nucleic Acids Research features descriptions of 96 new and 83 updated online databases covering various areas of molecular biology. It includes two editorials, one that discusses COMBREX, a new exciting project aimed at figuring out the functions of the ‘conserved hypothetical ’ proteins, and one concerning BioDBcore, a proposed description of the ‘minimal information about a biological database’. Papers from the members of the International Nucleotide Sequence Database collaboration (INSDC) describe each of the participating databases, DDBJ, ENA and GenBank, principles of data exchange within the collaboration, and the recently established Sequence Read Archive. A testament to the longevity of databases, this issue includes updates on the RNA modification database,

canSAR is a fully integrated cancer research and drug discovery resource developed to utilize the growing publicly available biological annotation, chemical screening, RNA interference screening, expression, amplification and 3D structural data. Scientists can, in a single place, rapidly identify biological annotation of a target, its structural characterization, expression levels and protein interaction data, as well as suitable cell lines for experiments, potential tool compounds and similarity to known drug targets. canSAR has, from the outset, been completely use-case driven which has dramatically influenced the design of the back-end and the functionality provided through the interfaces. The Web interface at

In many bacteria and archaea, small RNAs derived from clustered regularly interspaced short palin-dromic repeats (CRISPRs) associate with CRISPR-associated (Cas) proteins to target foreign DNA for destruction. In Type I and III CRISPR/Cas systems, the Cas6 family of endoribonucleases generates functional CRISPR-derived RNAs by site-specific cleavage of repeat sequences in precursor tran-scripts. CRISPR repeats differ widely in both sequence and structure, with varying propensity to form hairpin folds immediately preceding the cleavage site. To investigate the evolution of distinct mechanisms for the recognition of diverse CRISPR repeats by Cas6 enzymes, we determined crystal structures of two Thermus thermophilus Cas6 enzymes both alone and bound to substrate and product RNAs. These structures show how the scaffold common to all Cas6 endonucleases has evolved two binding sites with distinct modes of RNA recognition: one specific for a hairpin fold and the other for a single-stranded 50-terminal segment preceding the hairpin. These findings explain how divergent Cas6 enzymes have emerged to mediate highly selective pre-CRISPR-derived RNA processing across diverse CRISPR systems.

ABSTRACT We present here EKPD (http://ekpd.biocuckoo.org), a hierarchical database of eukaryotic protein kinases (PKs) and protein phosphatases (PPs), the key molecules responsible for the reversible phosphorylation of proteins that are involved in almost all aspects of biological processes. As extensive experimental and computational efforts have been carried out to identify PKs and PPs, an integrative resource with detailed classification and annotation information would be of great value for both experi-

Abstract not found

Three-dimensional domain swapping is a unique protein structural phenomenon where two or more protein chains in a protein oligomer share a common structural segment between individual chains. This phenomenon is observed in an array of protein structures in oligomeric conformation. Protein structures in swapped conformations perform diverse functional roles and are also associated with deposition diseases in humans. We have performed in-depth literature curation and structural bioinformatics analyses to develop an integrated knowledgebase of proteins involved in 3D domain swapping. The hallmark of 3D domain swapping is the presence of distinct structural segments such as the hinge and swapped regions. We have curated the literature to delineate the boundaries of these regions. In addition, we have defined several new concepts like ‘secondary major interface ’ to represent the interface properties arising as a result of 3D domain swapping, and a new quantitative measure for the ‘extent of swapping ’ in structures. The catalog of proteins reported in 3DSwap knowledgebase has been generated using an integrated structural bioinformatics workflow of database searches, literature curation, by structure visualization and sequence–structure–function analyses. The current version of

ABSTRACT Molecular Biology has been at the heart of the 'big data' revolution from its very beginning, and the need for access to biological data is a common thread running from the 1965 publication of Dayhoff's 'Atlas of Protein Sequence and Structure' through the Human Genome Project in the late 1990s and early 2000s to today's population-scale sequencing initiatives. The European Bioinformatics Institute (EMBL-EBI; http://www.ebi. ac.uk) is one of three organizations worldwide that provides free access to comprehensive, integrated molecular data sets. Here, we summarize the principles underpinning the development of these public resources and provide an overview of EMBL-EBI's database collection to complement the reviews of individual databases provided elsewhere in this issue. INTRODUCTION The molecular life sciences are becoming increasingly datadriven and reliant on open-access databases (1). This is as true of the applied sciences as it is of fundamental research: in the past year, we have witnessed announcements that the UK's National Health Service will invest in sequencing the genomes of up to 100 000 citizens (see http://www.gov.uk/ government/speeches/strategy-for-uk-life-sciences-one-yearon and http://news.sciencemag.org/biology/2012/12/u.k.-unveils-plan-sequence-whole-genomes-100000-patients); the Faroe Islands are planning to sequence the genome of every citizen who wishes to have this information (see http://www.fargen.fo/en/), and large-scale metagenomics projects are helping us to map the global biodiversity of the oceans (2). The European Bioinformatics Institute (EMBL-EBI), part of the European Molecular Biology Laboratory, makes these large-scale efforts possible. It helps scientists deposit their research data into public collections, produces value-added knowledge bases and makes its entire holdings accessible to all, thereby enabling millions of scientists worldwide to explore, analyse, interpret and derive new knowledge from decades of scientific endeavour. Among its other roles (Appendix 1), EMBL-EBI has a mission to provide free and open access to biomolecular information, spanning scientific literature and the data supporting it: DNA and protein sequences; biomolecules and their structures, functions, reactions and interactions; and practical tools for analysis and discovery. These offerings include personally identifiable genetic and phenotypic data resulting from biomedical research projects-an area of growing importance as healthcare systems embrace genomic medicine. Managing access to these data sets is a high-priority activity at EMBL-EBI. EMBL-EBI's core resources are foundational members of international consortia, which share data globally and foster competitiveness among their members. Some of these collaborations have a long history [e.g. the International Nucleotide Sequence Database Collaboration (INSDC) (3), the worldwide Protein Data Bank (wwPDB) (4), UniProt (5) and Ensembl (6)]. Others, driven by EMBL-EBI, are more recent [e.g. IMEx (7) for protein interaction data; ProteomExchange (8) for protein identification data and COSMOS (9) for metabolomics data]. The Global Alliance (10)-a large-scale international effort to enable the secure sharing of genomic and clinical data-is the most recent of these. Each of these collaborations exemplifies the fundamental principles of EMBL-EBI service provision (Appendix 2). DESIGNED TO BE USED EMBL-EBI embraces user-centred design (UCD), an approach that focuses on the behaviour and needs of the people who will actually use the product. UCD has been successfully applied to design in many different domains, although its application to bioinformatics services By placing the user at the forefront of our minds as we design, test and implement our services, we create more useful and user-friendly resources. This approach has been used to completely redesign the EMBL-EBI website-a major project that has involved every team at EMBL-EBI. The redesign puts users at the centre of the process, providing an intuitive new interface to EMBL-EBI services. It aims for consistent functionality without stifling the individual data resource brands. EMBL-EBI's search engine (14) displays results in an organized manner, according to the central dogma of molecular biology (i.e. DNA makes RNA makes protein). This results in an uncluttered results 'dashboard' from which users can explore genes, protein sequences, gene expression, molecular structures and related scientific literature. The search allows easy comparison of key information for human, mouse, fly and other species. Bioinformatics services on the EMBL-EBI website are displayed according to nine major themes LITERATURE Access to the scientific literature is a basic requirement for research. EMBL-EBI coordinates the development of Europe PubMed Central Europe (PMC) (15) in

3DSwap: curated knowledgebase of proteins