Systematic domain-based aggregation of protein structures highlights DNA-, RNA- and other ligand-binding positions.

TitleSystematic domain-based aggregation of protein structures highlights DNA-, RNA- and other ligand-binding positions.
Publication TypeJournal Article
Year of Publication2019
AuthorsKobren, SNadimpalli, Singh, M
JournalNucleic Acids Res
Volume47
Issue2
Pagination582-593
Date Published2019 01 25
ISSN1362-4962
KeywordsBinding Sites, Disease, DNA, DNA-Binding Proteins, Genes, Humans, Ligands, Models, Molecular, Mutation, Protein Binding, Protein Domains, RNA, RNA-Binding Proteins
Abstract

Domains are fundamental subunits of proteins, and while they play major roles in facilitating protein-DNA, protein-RNA and other protein-ligand interactions, a systematic assessment of their various interaction modes is still lacking. A comprehensive resource identifying positions within domains that tend to interact with nucleic acids, small molecules and other ligands would expand our knowledge of domain functionality as well as aid in detecting ligand-binding sites within structurally uncharacterized proteins. Here, we introduce an approach to identify per-domain-position interaction 'frequencies' by aggregating protein co-complex structures by domain and ascertaining how often residues mapping to each domain position interact with ligands. We perform this domain-based analysis on ∼91000 co-complex structures, and infer positions involved in binding DNA, RNA, peptides, ions or small molecules across 4128 domains, which we refer to collectively as the InteracDome. Cross-validation testing reveals that ligand-binding positions for 2152 domains are highly consistent and can be used to identify residues facilitating interactions in ∼63-69% of human genes. Our resource of domain-inferred ligand-binding sites should be a great aid in understanding disease etiology: whereas these sites are enriched in Mendelian-associated and cancer somatic mutations, they are depleted in polymorphisms observed across healthy populations. The InteracDome is available at http://interacdome.princeton.edu.

DOI10.1093/nar/gky1224
Alternate JournalNucleic Acids Res.
PubMed ID30535108
PubMed Central IDPMC6344845
Grant ListR01 CA208148 / CA / NCI NIH HHS / United States
R01 GM076275 / GM / NIGMS NIH HHS / United States