ArticlePLoS computational biology2010
The overlap of small molecule and protein binding sites within families of protein structures.
Article in PLoS computational biology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 46 citations in OpenAlex.
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- Elongation factor Tu is a multifunctional and processed moonlighting protein.Scientific reports · 2017Article
- Exploring Protein-Protein Interactions as Drug Targets for Anti-cancer Therapy with In Silico Workflows.Methods in molecular biology (Clifton, N.J.) · 2017Article
- Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.Nature reviews. Drug discovery · 2016Review
- DOMMINO 2.0: integrating structurally resolved protein-, RNA-, and DNA-mediated macromolecular interactions.Database : the journal of biological databases and curation · 2016Article
- PPDMs-a resource for mapping small molecule bioactivities from ChEMBL to Pfam-A protein domains.Bioinformatics (Oxford, England) · 2015Article
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- Biophysics of protein evolution and evolutionary protein biophysics.Journal of the Royal Society, Interface · 2014Article
- Drug-Like Protein-Protein Interaction Modulators: Challenges and Opportunities for Drug Discovery and Chemical Biology.Molecular informatics · 2014Review
- iPfam: a database of protein family and domain interactions found in the Protein Data Bank.Nucleic acids research · 2014Article
- Specialized Dynamical Properties of Promiscuous Residues Revealed by Simulated Conformational Ensembles.Journal of chemical theory and computation · 2013Article
- A compound-based computational approach for the accurate determination of hot spots.Protein science : a publication of the Protein Society · 2013Article
- Plucking the high hanging fruit: a systematic approach for targeting protein-protein interactions.Bioorganic & medicinal chemistry · 2013Article
- Exploring the composition of protein-ligand binding sites on a large scale.PLoS computational biology · 2013Article
- Article
- Physiology and pathophysiology of the blood-brain barrier: P-glycoprotein and occludin trafficking as therapeutic targets to optimize central nervous system drug delivery.Journal of investigative medicine : the official publication of the American Federation for Clinical Research · 2012Review
- Small-molecule inhibitor starting points learned from protein-protein interaction inhibitor structure.Bioinformatics (Oxford, England) · 2012Article
- Visualisation of variable binding pockets on protein surfaces by probabilistic analysis of related structure sets.BMC bioinformatics · 2012Article
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
Protein-protein interactions are challenging targets for modulation by small molecules. Here, we propose an approach that harnesses the increasing structural coverage of protein complexes to identify small molecules that may target protein interactions. Specifically, we identify ligand and protein binding sites that overlap upon alignment of homologous proteins. Of the 2,619 protein structure families observed to bind proteins, 1,028 also bind small molecules (250-1000 Da), and 197 exhibit a statistically significant (p<0.01) overlap between ligand and protein binding positions. These "bi-functional positions", which bind both ligands and proteins, are particularly enriched in tyrosine and tryptophan residues, similar to "energetic hotspots" described previously, and are significantly less conserved than mono-functional and solvent exposed positions. Homology transfer identifies ligands whose binding sites overlap at least 20% of the protein interface for 35% of domain-domain and 45% of domain-peptide mediated interactions. The analysis recovered known small-molecule modulators of protein interactions as well as predicted new interaction targets based on the sequence similarity of ligand binding sites. We illustrate the predictive utility of the method by suggesting structural mechanisms for the effects of sanglifehrin A on HIV virion production, bepridil on the cellular entry of anthrax edema factor, and fusicoccin on vertebrate developmental pathways. The results, available at http://pibase.janelia.org, represent a comprehensive collection of structurally characterized modulators of protein interactions, and suggest that homologous structures are a useful resource for the rational design of interaction modulators.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.