Universiteit Leiden

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Research project

Receptor bioinformatics and pharmacogenomics

Research question

Contact
Gerard van Westen

Many medicines act via protein targets in the human body. Thus drugs against high blood pressure and asthma, to treat depression and Parkinson's disease, drugs that act as painkillers, all modulate beneficially selected proteins in our body. Most of these medicines have a preference for a particular family of proteins present in the membrane of virtually all cells, so-called G protein-coupled receptors (GPCRs). The human genome projects predict that there are some 800 of these, many of which the function and role is yet to be determined (orphan receptors). Research groups in Leiden (the Leiden Academic Center for Drug Research - LACDR) and Nijmegen (Center for Molecular Bioinformatics - CMBI) have spent considerable time and effort on well-known and orphan receptors. This has resulted in the making of a dedicated database for these receptors, called the GPCRDB. Being freely available on the internet, the database is consulted by scientists from all over the world, both from industry and academia, and currently maintained by the University of Copenhagen.

Our work has focused on algorithms to mine GPCR sequences with the aim to identify residues that are, for example, conserved in a particular family of receptors - and which are thus (probably) essential for its function. On the other hand, one can watch out for residues that are very little conserved in those receptors - and which are possible associated with selectivity of the receptor for a particular group of ligands. This analysis was termed 'two-entropies analysis' and it was the work of Dr. Kai Ye's PhD thesis (2008).

Given the relative ease with which individual whole genomes can now be sequenced, we have currently taken a new approach. The aim is to focus on individual differences in the GPCR genome, and learn whether such differences have medical relevance. Here we collaborate with leading sequencing groups in the Netherlands, VUmc (Prof D. Boomsma, Twin Register) en LUMC (Prof. E. Slagboom, GoNL). A first publication has recently appeared.

 

Image adapted from: van Westen, Gerard JP, et al. "Benchmarking of protein descriptor sets in proteochemometric modeling (part 1): comparative study of 13 amino acid descriptor sets." Journal of cheminformatics 5.1 (2013): 1.

Ye, K., Lameijer, E. W. M., Beukers, M. W., & IJzerman, A. P. (2006). A two‐entropies analysis to identify functional positions in the transmembrane region of class AG protein‐coupled receptors. Proteins: Structure, Function, and Bioinformatics, 63(4), 1018-1030.

Hillger, J. M., Schoop, J., Boomsma, D. I., Slagboom, P. E., IJzerman, A. P., & Heitman, L. H. (2015). Whole-cell biosensor for label-free detection of GPCR-mediated drug responses in personal cell lines. Biosensors and Bioelectronics, 74, 233-242.

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