Missense3D-PTMdb an interactive web resource to explore and visualize genetic variants and post-translational modifications sites (PTMs) using AlphaFold 3D models

Only a fraction of the >11 million missense variants identified in the human population has a known damaging or tolerated clinical impact. Post-translational modifications (PTMs), such as phosphorylation, glycosylation and ubiquitination, are key regulators of protein function and structure, and are critical for protein localisation, stability and interactions with other molecules. The ability of a protein to undergo PTMs, is subject to a correctly folded protein structure, and the recognition and binding of enzymes to specific amino acid motifs in close proximity to residues that undergo PTMs [PTM residue]. AlphaFold models provide an unprecedented opportunity to perform sequence-structure mapping of variants, which are in close linear or spatial proximity to a PTM site and should have their impact on protein function experimentally investigated.

We present Missense3D-PTMdb, a “one-stop-shop” interactive web tool that provides a user-friendly sequence-structure mapping of 20,235 human proteins to 11,544,303 naturally occurring human missense variants, 203,775 PTM sites and their neighbours in sequence and 3D structure space using AlphaFold generated 3D models of the human proteome. Additionally, the sequence-structure mapping tool allows visualization and exploration of any human variant not currently stored in the database. Missense3D-PTMDb is freely available at https://missense3d.bc.ic.ac.uk/ptmdb .