1. CryptoSite: Expanding the Druggable Proteome by Characterization and Prediction of Cryptic Binding Sites
- Author
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Andrej Sali, Julie C. Mitchell, Rahel A. Woldeyes, Peter Cimermancic, Daniel A. Keedy, T. Justin Rettenmaier, Dina Schneidman-Duhovny, James S. Fraser, Leon Bichmann, Patrick Weinkam, James A. Wells, and Omar N. A. Demerdash
- Subjects
0301 basic medicine ,Biochemistry & Molecular Biology ,Conformational change ,Proteome ,Protein Conformation ,Druggability ,Computational biology ,Biology ,010402 general chemistry ,Microbiology ,01 natural sciences ,Article ,Vaccine Related ,Machine Learning ,Medicinal and Biomolecular Chemistry ,03 medical and health sciences ,Structural Biology ,Human proteome project ,Humans ,cryptic binding sites ,undruggable proteins ,Binding site ,Molecular Biology ,Binding Sites ,Protein dynamics ,Proteins ,Computational Biology ,Molecular biology ,0104 chemical sciences ,A-site ,machine learning ,030104 developmental biology ,Docking (molecular) ,protein dynamics ,Generic health relevance ,Biochemistry and Cell Biology - Abstract
Many proteins have small molecule-binding pockets that are not easily detectable in the ligand-free structures. These cryptic sites require a conformational change to become apparent; a cryptic site can therefore be defined as a site that forms a pocket in a holo structure, but not in the apo structure. Because many proteins appear to lack druggable pockets, understanding and accurately identifying cryptic sites could expand the set of drug targets. Previously, cryptic sites were identified experimentally by fragment-based ligand discovery, and computationally by long molecular dynamics simulations and fragment docking. Here, we begin by constructing a set of structurally defined apo-holo pairs with cryptic sites. Next, we comprehensively characterize the cryptic sites in terms of their sequence, structure, and dynamics attributes. We find that cryptic sites tend to be as conserved in evolution as traditional binding pockets, but are less hydrophobic and more flexible. Relying on this characterization, we use machine learning to predict cryptic sites with relatively high accuracy (for our benchmark, the true positive and false positive rates are 73% and 29%, respectively). We then predict cryptic sites in the entire structurally characterized human proteome (11,201 structures, covering 23% of all residues in the proteome). CryptoSite increases the size of the potentially “druggable” human proteome from ~40% to ~78% of disease-associated proteins. Finally, to demonstrate the utility of our approach in practice, we experimentally validate a cryptic site in protein tyrosine phosphatase 1B using a covalent ligand and NMR spectroscopy. The CryptoSite web server is available at http://salilab.org/cryptosite.
- Published
- 2016