Science | Ralf Flaig

Ralf Flaig
Macromolecular Crystallography

Ralf Flaig Ralf Flaig is Beamline Scientist on the Macromolecular Crystallography Beamline I04 and also a visiting scientist of the Department of Biochemistry at the University of Oxford. Before joining Diamond he was a Postdoc at the IGBMC in Strasbourg. His main research interest is the analysis of the electron density distribution and related properties of both small and macro-molecules and the elucidation of structure-function relationships of macromolecules with an important biological interest and applications in drug design.

Email: Ralf Flaig
Tel: +44 (0) 1235 778412
Beamlines: Macromolecular Crystallography

Key Research Areas

High resolution crystallography, macromolecular crystallography, molecular modelling, transcription, cell cycle control

Current Research Interests

My recent research has concentrated on nuclear receptors (NRs), a superfamily of transcription factors which are in most cases ligand-induced, for example the receptors for steroid hormones and retinoids. They regulate many complex physiological processes and events that control key steps during development, control of homeostasis and cellular proliferation, differentiation and apoptosis. X-ray structure determination of the ligand-binding domains of nuclear receptors revealed the major principles of ligand-dependent action of NRs and determinants of selective ligand binding. In combination with functional studies, this led to an increasing knowledge on the structure-activity relationship of ligand-regulated NRs. This is important since the ligand dependent activity of these proteins make them ideal targets for drug design in many therapeutic areas.

Besides the large number of nuclear receptors which are controlled by a signalling molecule, numerous receptors have been identified for which no ligand is known to date. These include nuclear receptors which play an important role in the nervous system and neurodegenerative diseases like Parkinson’s. Our research showed however that structure determination by macromolecular crystallography reveals distinct differences in the molecular conformation. In addition, we also identified a novel co-regulator surface. These findings helped to explain transactivation properties and cell-specific activities for this class of molecules.

For many nuclear receptors there exist various isotypes for the same receptor, e.g in the family of retinoid receptors or estrogen-related receptors. These isotypes differ in their ligand-binding properties as well as in their interaction with various cofactors. Comparative structural and functional studies of these proteins bound to different ligands and cofactors allowed us to understand and explain their isotype selectivity. We conducted studies which provided detailed molecular insight into the changes that occur upon ligand binding and revealed structural differences between isotypes as well as between different receptor families. These findings will help to design new selective drug molecules.

Another focus of my research is high and ultra-high resolution crystallography which allows the accurate determination of the charge or electron density distribution of molecules. From this it is possible to derive related electronic and electrostatic properties, like dipole and multipole moments or the electrostatic potential. In addition this permits a detailed study of intra- and intermolecular interactions. These properties are widely used in molecular modelling to study protein-ligand interactions, e.g. the binding of a drug molecule to its receptor. Understanding molecular recognition and binding interactions are key elements of structure based drug design.

Selected Publications

  1. "Accurate Experimental Electronic Properties of DL-Proline Monohydrate Obtained Within 1 Day", T. Koritsánszky, R. Flaig, D. Zobel, H.-G. Krane, W. Morgenroth, P. Luger, Science 279 (1998), 356-358
  2. "Topological Analysis of the Experimental Electron Densities of Amino Acids. 1. DL-Aspartic Acid at 20 K", R. Flaig, T. Koritsánszky, D. Zobel, P. Luger, J. Am. Chem. Soc. 120 (1998), 2227-2238
  3. "Electronic Insight into an Antithrombotic Agent by High-resolution X-ray Crystallography", R. Flaig, T. Koritsánszky, R. Soyka, L. Häming, P. Luger, Angew. Chem. Int. Ed. 40 (2001), 355-359
  4. "Structural Basis for the Deactivation of the Estrogen-related Receptor gamma by Diethylstilbestrol or 4-Hydroxytamoxifen and Determinants of Selectivity.", H. Greschik, R. Flaig, J-P. Renaud, D. Moras, J. Biol. Chem. 279 (2004), 33639-33646
  5. "Structural Basis for the Cell-specific Activities of the NGFI-B and the Nurr1 Ligand-binding Domain", R. Flaig, H. Greschik, C. Peluso-Iltis, D. Moras, J. Biol. Chem. 280 (2005), 19250-19258

  6. New light for science: synchrotron radiation in structural medicine, T L-M Sorensen, KE McAuley, R Flaig, EM Duke, Trends in Biotechnology (2006) 24:500-8