Universiteit Leiden

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Research project

Mutating GPCRs

Supervisors: Willem Jespers (Uppsala University), Gerard van Westen (LACDR), David Gloriam (Copenhagen University)

Gerard van Westen

Literature study Medicinal Chemistry

Mutagenesis experiments on G Protein-Coupled Receptors (GPCR’s) have been performed for over 30 years for multiple applications (e.g. identifying the effect of certain residues on ligand binding1, increasing (thermo)stability of a receptor and characterization of GPCR functionality2). Mutagenesis data thus can provide crucial insights for researchers involved with GPCR’s. However a major problem is the availability of high quality data. Recently an effort has been made towards the collection and curation of high quality mutagenesis data through the GPCR database (GPCRdb), which has served the GPCR community for more than 20 years. 3,4

The objective of this literature study is to collect and analyze mutagenesis data of a GPCR of selected GPCRs. The first two weeks will be used to collect all available literature data on this receptor. Collected data will be uploaded to the GPCRdb and used for further analysis, which is fully automated, for the further writing of the literature study (figure 1).

This literature study could be used as a starting point for other internships at any of the involved labs (Copenhagen, Uppsala or Leiden University). A recent publication on the metabotropic glutamate receptors shows that this type of reviews, without new data, can be published in (high impact) papers.3

(1) Salon, J. A.; Lodowski, D. T.; Palczewski, K. The Significance of G Protein-Coupled Receptor Crystallography for Drug Discovery. Pharmacol. Rev. 2011, 63 (4), 901–937.

(2) Roth, C. B.; Hanson, M. A.; Stevens, R. C. Stabilization of the Human beta2-Adrenergic Receptor TM4-TM3-TM5 Helix Interface by Mutagenesis of Glu122(3.41), a Critical Residue in GPCR Structure. J.Mol. Biol. 2008, 376 (5), 1305–1319.

(3) Harpsøe, K.; Isberg, V.; Tehan, B. G.; Weiss, D.; Arsova, A.; Marshall, F. H.; Bräuner-Osborne, H.; Gloriam, D. E. Selective Negative Allosteric Modulation Of Metabotropic Glutamate Receptors – A Structural Perspective of Ligands and Mutants. Sci. Rep. 2015, 5 (January), 13869.

(4) Isberg, V.; Vroling, B.; van der Kant, R.; Li, K.; Vriend, G.; Gloriam, D. GPCRDB: An Information System for G Protein-Coupled Receptors. Nucleic Acids Res. 2014, 42 (Database issue), D422–D425.

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