Christina Mølck

Jan. 2010 - present:     
PhD student (DRA PhD studentships) at the University of Copenhagen, Faculty of pharmaceutical sciences, Department of medicinal chemistry

2009:                   
MSc (Pharm) at the University of Copenhagen, Faculty of pharmaceutical sciences, Department of Pharmacology and Pharmacotherapy

Sep. 2008 – May 2009:
Laboratory assistant at H. Lundbeck A/S (Valby) in Research Support Services

Feb. 2008 – Jul. 2008:
Internship at Randers Jernbane Pharmacy

2007:
BSc (Pharm) at the University of Copenhagen, Faculty of pharmaceutical sciences

Studies on the molecular mechanisms of ligand binding and activation of the G protein-coupled receptor mGluR5

Background: Seven transmembrane (7TM) G protein-coupled receptors (GPCRs) constitute the largest superfamily of cell-surface proteins. GPCRs are characterized by a bundle of 7TM helixes, each containing highly conserved residues, which divide GPCRs into several families including family A (rhodopsin-like) and family C (metabotropic glutamate-like) receptors. Despite the same overall topology, family A and family C receptors differ especially in terms sequence identity in the 7TM region and the amino-terminal region, which for the family C receptors contains the so-called venus-flytrap domain (VTD) of the family C receptors.

GPCRs constitute one of the most important classes of drug targets as approximately 40% of marketed drugs including a majority of the most sold drugs target these proteins. The marketed drugs targeting GPCRs is logically dominated by the family A receptors, as this family by far is the quantitatively dominating and as well as the most extensively studied family of receptors. However, drugs targeting other families including family C receptors are involved in clinical programs¹ and interestingly, in addition to the traditional kind of pharmacological profiles like agonism and antagonism, the profile of drugs targeting family C receptors also includes allosteric modulation^2,3. This type of profile are from a therapeutic point of view very interesting as modulators are e.g. likely to display a different side effect profile since these are expected to be efficacious only in presence of endogenous agonists.

Despite successful drug discovery activities, insight into ligand binding to and activation of the 7TM domain of family C receptors is missing. This contrasts the rather detailed knowledge of the family A receptors, for which crystal structures of inactive and partially active receptor conformations and biophysical studies of the movements involved in activation of the 7TM region are available⁴. This detailed insight into the molecular mechanism of 7TM ligand binding and receptor activation have significant impact on e.g. rational drug design and high throughput docking activities for family A receptors⁵.

Objectives: Therefore, inspired by the successful achievements in the family A receptor field, the goals of this project are to gain insight into the molecular mechanism of ligand binding and activation of the 7TM region of family C receptors using the mGluR5 receptor as a representative by:

1) characterizing binding sites of positive and negative modulators of the mGluR5 receptor (in conjunction with on-going 7TM modeling activities at Mt Sinai).

2) conduct biophysical experiments of the mGluR5 receptor in order to delineate TM movements during activation with orthosteric agonist and positive modulators.

1.   Patil, S. T. et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat. Med 13, 1102-1107 (2007).

2.   Yano, S. et al. Bone metabolism after cinacalcet administration in patients with secondary hyperparathyroidism. J Bone Miner. Metab. (2009).

3.   Jensen, A. A. & Brauner-Osborne, H. Allosteric modulation of the calcium-sensing receptor. Curr. Neuropharmacol. 5, 180-186 (2007).

4.   Gether, U. et al. Agonists induce conformational changes in transmembrane domains III and VI of the beta2 adrenoceptor. EMBO J 16, 6737-6747 (1997).

5.   Sabio, M., Jones, K. & Topiol, S. Use of the X-ray structure of the beta2-adrenergic receptor for drug discovery. Part 2: Identification of active compounds. Bioorg. Med Chem. Lett. 18, 5391-5395 (2008).

6.   Lindsley, C. W. et al. Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H- pyrazol-5-yl)benzamides that potentiate receptor function in vivo. J Med Chem. 47, 5825-5828 (2004).

7.   O'Brien, J. A. et al. A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5. Mol Pharmacol 64, 731-740 (2003).

8.  Yao X., et al. The effect of ligand efficacy on the formation and stability of a GPCR-G protein complex. PNAS 106, 9501-9506 (2009)

Main advisor:
Hans Bräuner-Osborne

Co-advisors:
Søren Møller Nielsen (H. Lundbeck A/S)
Jesper Mosolff Mathiesen

H. Lundbeck A/S