Integration of data on diseases and drugs associated with PTM substrate sites

Many proteins undergo PTMs that involve physical or chemical changes to their side chains, causing cancer or other diseases; other PTMs may be used diagnostically. Accordingly, the disease annotations in the KEGG Disease Database, the Online Mendelian Inheritance in Man database (OMIM) and Human Protein Reference Database (HPRD) were integrated to identify associations between diseases and PTM-associated proteins. Despite the fact that more than 60% of eukaryotic proteins undergo PTMs during or after protein biosynthesis, little is known about the frequency and local effects of PTMs close to drug or inhibitor-binding sites. A phosphorylation site within 12 A of a small molecule-binding site is reportedly likely to alter the binding affinity of this small molecule. Therefore, the drug annotations in DrugBank were combined with all available PDB entries that contained keywords ‘drug,’ ‘inhibitor,’ ‘agonist’ or ‘antagonist’. After all experimentally verified PTM sites were mapped to PDB structures, the PTM sites whose side chains are located within 10 A of a drug-binding site were regarded as drug binding-associated PTMs. Based on a large-scale screening of PTM sites and drug-binding sites in PDB, over 1100 PTM sites that are associated with drug-binding sites were identified.

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