Comprehensive structural classification of ligand binding motifs in proteins

TL;DR

This study systematically classifies protein ligand binding motifs by comparing over 180,000 sites, revealing their structural diversity, family-specificity, and cross-fold similarities, aiding functional annotation and drug design.

Contribution

It provides a comprehensive structural classification of ligand binding motifs, identifying approximately 3000 distinct motifs and their cross-family similarities.

Findings

Most motifs are family-specific and ligand-associated.

Identified over 4000 cross-fold ligand site pairs.

Constructed a detailed network of binding site similarities.

Abstract

Comprehensive knowledge of protein-ligand interactions should provide a useful basis for annotating protein functions, studying protein evolution, engineering enzymatic activity, and designing drugs. To investigate the diversity and universality of ligand binding sites in protein structures, we conducted the all-against-all atomic-level structural comparison of over 180,000 ligand binding sites found in all the known structures in the Protein Data Bank by using a recently developed database search and alignment algorithm. By applying a hybrid top-down-bottom-up clustering analysis to the comparison results, we determined approximately 3000 well-defined structural motifs of ligand binding sites. Apart from a handful of exceptions, most structural motifs were found to be confined within single families or superfamilies, and to be associated with particular ligands. Furthermore, we analyzed the components of the similarity network and enumerated more than 4000 pairs of ligand binding sites that were shared across different protein folds.