3D-Gateway to protein structure and function

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Despite significant advances in protein structure determination, the majority of proteins have no experimental structural data. Significant improvements in structure prediction methods can fill this gap and provide valuable data for understanding protein functions. Presently, structure data are archived in distinct resources (the PDB for experimental structures, and Genome3D and other specialist resources for predicted models) impeding their access by the wider user community. The 3D-Beacons infrastructure will allow seamless access to all structure models providing a mechanism for maximising structural coverage of UniProtKB.

The 3D-Beacons network will also simplify the comparison of models from different model repositories, allowing development of better confidence measures. Collaboration of resources will ensure the sustainability of the system, and the proposed uniform data access mechanism (REST API) will simplify integration of structural data by other resources such as InterPro and Ensembl and tools such as JalView, Chimera, Pymol to provide an essential foundation for understanding the impacts of genetic variations on protein functions. Access to model structures is also valuable in structure determination and analysis pipelines.

We will also develop mechanisms for transferring structure-based functional annotations from the PDBe Knowledgebase to UniProt proteins, and derive a confidence measure for the annotations. This infrastructure will allow integration and display of these annotations for UniProt sequences from key model organisms including important agricultural organisms and their pathogens.

Furthermore, these functional annotations will be built into the UniProt UniRule system enabling both (i) large scale annotation of the UniProt KnowledgeBase (UniProtKB) and (ii) their use by other groups annotating completed genomes or metagenome data, through the UniFIRE (the UNIprot Functional annotation Inference Rule Engine) system.

Protein structure data provides valuable insights into the mechanisms by which proteins function and can thus provide explanation for impacts of genetic variation. It also aids drug design and protein engineering e.g. for greater stability or higher catalytic efficiency. The impact of structural data is evident from the significant uptake of the data by the community. For example, structural data in PDBe is accessed by >60,000 unique users/month. Genome3D is an integrated resource with structural data from 5 world-leading UK resources, whose sites typically attract 10,000 - 15,000 users/month. The Genome3D data is also disseminated via InterPro which has 135,000 unique users/month.

Despite significant advances in protein structure determination, a significant proportion of proteins have no experimental structural data in the PDB. However, protein structure prediction methods have improved significantly and the models produced can provide valuable data for understanding protein functions and the impacts of genetic variations. By expanding the predicted structural data in Genome3D and implementing the 3D-Beacon network to integrate additional predicted data from other internationally acclaimed resources (i.e. ModBase, Rosetta, SWISS-MODEL), we will maximise the structural coverage of sequences in UniProtKB and provide valuable data benefitting a very wide community of biologists. As well as aggregating known/predicted structural data, 3D-Beacon network will aggregate structure-based functional annotations from PDBe-KB. Our 3D-Gateway pages will be carefully designed to display all this information for a given UniProt sequence, in a highly intuitive manner that makes the source of, and confidence in, the data clear. The impact of UniProt in the biological community is extremely high, with access by >750,000 biologists each month.

Our project has clear deliverables likely to have impact on research studies:
(1) 3D-Beacon network based aggregation of structural and functional data will also allow individual groups to download aggregated structural data for sets of UniProt proteins. This gives a mechanism for other data providers, e.g. Interactome3D, to combine the data with their information, e.g. on protein interactions and drug targets.
(2) Dedicated 3D-Gateway webpages showing structural and functional annotations will provide biologists access to functional information on a protein they are studying. In this context information provided by UniProt on known disease variants will be enriched by structural and functional information, provided by our 3D-Gateway project, highlighting key residues.
(3) The incorporation of structural and functional annotations in UniRules will allow safe transference of annotations to an even greater set of UniProt sequences and these rules will also be available to genome curators to enable functional annotation and comparative genome studies.

Industry will also benefit from the structural and functional annotations of UniProt sequences on the 3D-Gateway pages, to guide drug design.

As an activity in the ELIXIR Community of Structural Bioinformatics, 3D-Beacons will make the aggregated data available to groups across Europe and beyond, who in turn will contribute their own data to 3D-Beacons for display on the web pages. This community will also be involved in exploring mechanisms to ensure the quality of the aggregated data (e.g. by highlighting outlying data and developing sound confidence measures).

Furthermore, the ELIXIR 3D-BioInfo Community is building links with the ELIXIR Rare Disease and Galaxy Communities to develop workflows for accessing known and predicted structural data. ELIXIR funding is already supporting development of web-based training workflows in TESS, by PDBe and Genome3D, for exploiting structural data to gauge the impacts of genetic variations. This training material will ensure wider uptake and exploitation of data from the 3D-Gateway project.