COSMIC-3D provides structural perspectives on cancer genetics for drug discovery

Abstract

COSMIC-3D is a comprehensive integration of cancer mutations with protein structure across the human genome and structural proteome, seeking to support the identification and characterisation of protein targets for novel drug design in precision oncology. As an interactive system to explore cancer mutations in three-dimensions, COSMIC-3D is designed to enable a greater understanding of the functional impact of mutations, generate new hypotheses on which mutations are cancer drivers, and provide new opportunities for addressing these mutations pharmaceutically. This combination of genetics, structural proteomics, and drug development, can be best described as “mutation-guided drug design”.

Figure 1

Individual views of mutation, mutation frequency, and protein sequence views in COSMIC-3D. a) COSMIC-3D structure visualisation of EGFR protein’s kinase domain ATP binding site, showing Leu858 in pink, and an in silico generated model of oncogenic mutant Arg858 in orange. Mutation visualisations are juxtaposed with the highest ranked druggable binding site prediction (blue volume), which accurately encompasses the laptanib binding site (shown in stick representation). Individual missense mutation visualisations can be displayed by clicking on them in the sequence feature viewer. Predicted small molecule binding sites and their druggability can be displayed using the controls in the “Predicted Small-Molecule Binding Sites” section for the active protein structure. PDB: 1XKK. b) TP53 protein DNA binding domain tetramer bound to DNA, visualised with missense mutation recurrence analysis in COSMIC-3D. Recurrence of missense mutations is shown as surfaces coloured on a linear scale, where yellow indicates low recurrence in COSMIC, and red indicates high recurrence. Clearly, the most frequent missense mutations are affecting DNA binding functions. PDB: 4HJE. c) Example of the COSMIC-3D protein sequence feature view for BRAF (NP_004324.2). The 2D sequence view is linked to 3D structure, showing structural coverage of the protein sequence, a graph of missense mutation recurrence, and a “waterfall” of COSMIC mutations which can be clicked on for 3D visualisation. UniProt features add additional context to the structural and functional relevance of COSMIC mutations in proteins.