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Open Access Research article

ss-TEA: Entropy based identification of receptor specific ligand binding residues from a multiple sequence alignment of class A GPCRs

Marijn PA Sanders1, Wilco WM Fleuren1, Stefan Verhoeven2, Sven van den Beld1, Wynand Alkema2, Jacob de Vlieg12 and Jan PG Klomp2*

Author Affiliations

1 Computational Drug Discovery Group, Radboud University Nijmegen Medical Centre, Geert Grooteplein, Nijmegen, The Netherlands

2 Department of Molecular Design and Informatics, MSD, Molenweg, Oss, The Netherlands

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BMC Bioinformatics 2011, 12:332  doi:10.1186/1471-2105-12-332

Published: 10 August 2011

Abstract

Background

G-protein coupled receptors (GPCRs) are involved in many different physiological processes and their function can be modulated by small molecules which bind in the transmembrane (TM) domain. Because of their structural and sequence conservation, the TM domains are often used in bioinformatics approaches to first create a multiple sequence alignment (MSA) and subsequently identify ligand binding positions. So far methods have been developed to predict the common ligand binding residue positions for class A GPCRs.

Results

Here we present 1) ss-TEA, a method to identify specific ligand binding residue positions for any receptor, predicated on high quality sequence information. 2) The largest MSA of class A non olfactory GPCRs in the public domain consisting of 13324 sequences covering most of the species homologues of the human set of GPCRs. A set of ligand binding residue positions extracted from literature of 10 different receptors shows that our method has the best ligand binding residue prediction for 9 of these 10 receptors compared to another state-of-the-art method.

Conclusions

The combination of the large multi species alignment and the newly introduced residue selection method ss-TEA can be used to rapidly identify subfamily specific ligand binding residues. This approach can aid the design of site directed mutagenesis experiments, explain receptor function and improve modelling. The method is also available online via GPCRDB at http://www.gpcr.org/7tm/ webcite.