To provide examples on how the web server can be used for protein binding site prediction, we illustrate some case studies used to analyse protein-drug interactions in different perspectives.
G protein-coupled receptors (GPCR) is a large protein family of transmembrane proteins with diverse functions. The proteins are diverse in sequence and function and can be further separated into different groups. The rhodopsin-like GPCRs (Pfam family '7tm_1') consists of a set of proteins including hormones, neurotransmitters and receptors which mostly involve with small molecule binding. GPCRs, or 7-transmembrane (7-TM) receptors are important drug targets, with more than 30% of FDA-approved drugs are bound to these proteins.
From the ‘Search for drug binding interfaces in protein-drug complexes’ interface, keyword search for ‘7tm_1’ under 'Pfam annotation' category returns a list of known binding sites from proteins with Pfam annotation '7tm_1' or PF00001. User may filter the list based on ligand name or number of residues.
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The fifth column ('Macromolecule name') shows the macromolecule name of the protein structure as derived from the PDB. Scanning through the column, the '7tm_1' keyword search mapped to different structures, such as adrenergic receptor, muscarinic acetylcholine receptor and adenosine receptor.
The third column ('Ligand') shows drug molecule that are bound to respective receptors. Scanning through the column, GPCRs can bind to different drug molecules, such as Caffeine and Dobutamine.
Clicking one of the Macromolecule name, for example 'BETA-1 ADRENERGIC RECEPTOR', will open a new results page indicating a list of known binding sites for the query macromolecule.
Beta-1 adrenergic receptor binds to various drug molecules such as Dobutamine, Isoprenaline, Salbutamol and Carvedilol.
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Clicking on the DrReposER ID, for example '2Y00_A_Y00A601', will open a new results page with a list of similar patterns of amino acids derived from ASSAM searches.
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1) Felix, A. K. & Overington, J. P. (2012). Global Analysis of Small Molecule Binding to Related Protein Targets. PLoS Comput Biol. 8(1):e1002333. (link)
2) Hauser et al. (2018). Pharmacogenomics of GPCR Drug Targets. Cell. 172(1-2):41-54. (link)
3) Sriram, K. & Insel, P. A. (2018). G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs?. Mol Pharmacol. 93(4):251-258. (link)
4) Pfam annotation for 7 transmembrane receptor. (link)