Ralf Flaig

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Ralf Flaig is Senior Beamline Scientist on the MX beamline I04 and also an academic visitor of the Department of Biochemistry at the University of Oxford. Before joining Diamond in 2004 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@diamond.ac.uk
Tel: +44 (0) 1235 778412

Key Research Area

Other Specialist Areas

  • histone modification

 

Latest Publications

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  1. Research Expertise
  2. Collaborations
  3. Publications
  4. Biography
Research Expertise -

Current Research Interests

Image Current Research Interests

Epigenetic modifications (reversible, heritable genetic changes that occur without changes in DNA sequence) lead to chromatin remodelling, altered gene expression and changes in the cellular phenotype and therefore have been linked to a number of pathologies, including cancer, cardiac disease, neurological disorders, infections and inflammatory diseases. One epigenetic process is histone modification. This is important since gene regulation in eukaryotes requires the coordinate interaction of chromatin-modulating proteins with specific transcription factors. Gene activation and repression is specifically regulated by histone modification at distinct residues. Understanding these mechanisms can therefore provide new and specific theraphies for pathologies caused by these processes.

Structural characterisation and drug design of epigenetic regulators
Currently, my research projects focus on two protein families which have been identified as potential therapeutic targets. One aim is to investigate the structure and function of proteins binding to histone modifying proteins and another aim is to structurally characterise potential inhibitors of lysine demethylases and histone acetylases and elucidate the structural and functional relationships between these proteins and potential small molecule inhibitors, therefore aiding the process of finding potential drug molecules by structure-based optimisation that could possibly enter the step of pre-clinical assessment. The project involves the use of established biochemistry and molecular biology techniques and structure determination by X-ray crystallography.

I am developing the implementation of multi-axis goniometry in conjunction with suitable beam diagnostics and beam delivery in order to enable reliable and sophisticated data collection strategies for macromolecular crystals with the aim to push the limits of structure solution.

My role entails the operation and development of the macromolecular beamline (MX) I04 in particular, with contributions to other MX beamlines, user support and research projects in the area of structural biology and beamline technique development, in particular multi-axis goniometry, beam diagnostics and beam delivery implementation, organisation of meetings, and project management.

Collaborations - +

Collaborations

  1. Prof. Roland Schuele, University Medical Centre Freiburg (Germany)
    Epigenetic modifications
    My role is covering the aspects of structural biology
  2. Prof. Manfred Jung, Institute of Pharmaceutical Sciences, University of Freiburg (Germany)
    Drug development of epigenetic regulators
    My role is the structural characterisation of protein ligand complexes
  3. Prof. Ray Owens, OPPF-UK, University of Oxford
    Drug development of epigenetic regulators and histone-modifying proteins
    My role is covering the aspects of structural biology

 

Publications - +

Publications

Robaa, D., Wagner, T., Luise, C., Carlino, L., McMillan, J., Flaig, R., Schüle, R., Jung, M., Sippl, W.
Identification and Structure-Activity Relationship Studies of Small-Molecule Inhibitors of the Methyllysine Reader Protein Spindlin1
ChemMedChem, 11, 2327-2338 (2016)
doi: 10.1002/cmdc.201600362

Roatsch, M., Robaa, D., Pippel, M., Nettleship, JE., Reddivari, Y., Bird, LE., Hoffmann, I., Franz, H., Owens, RJ., Schüle, R., Flaig, R., Sippl, W., & Jung, M.
Substituted 2-(2-aminopyrimidin-4-yl)pyridine-4-carboxylates as potent inhibitors of JumonjiC domain-containing histone demethylases
Future Medicinal Chemistry, 8, 1553-1571 (2016)
doi: 10.4155/fmc.15.188

Metzger, E., Willmann, D., McMillan, J., Forne, I., Metzger, P., Gerhardt, S., Petroll, K., von Maessenhausen, A., Urban, S., Schott, A-K., Espejo, A., Eberlin,A., Wohlwend, D., Schüle, KM., Schleicher, M., Perner, S., Bedford,MT., Jung, M., Dengjel, J., Flaig, R., Imhof, A.,Einsle, O. & Schüle, R.
Assembly of methylated KDM1A and CHD1 drives androgen receptor–dependent transcription and translocation
Nature Structural & Molecular Biology, 23, 132–139 (2016)
doi: 10.1038/nsmb.3153

Aller, P., Sanchez-Weatherby, J., Foadi, J., Winter, G., Lobley, C.M., Axford, D., Ashton, A.W., Bellini, D., Brandao-Neto, J., Culurgioni, S., Douangamath, A., Duman, R., Evans, G., Fisher, S., Flaig, R., Hall, D.R., Lukacik, P., Mazzorana, M., McAuley, K.E., Mykhaylyk, V., Owen, R.L., Paterson, N.G., Romano, P., Sandy, J., Sorensen, T., von Delft, F., Wagner, A., Warren, A., Williams, M., Stuart, D.I., Walsh, M.A.
Application of in situ diffraction in high-throughput structure determination platforms
Methods Mol Biol., 1261, 233-53 (2015). doi: 10.1007/978-1-4939-2230-7_13

Duke, E.H.M., Evans, G., Flaig, R., Hall, D.R., Latchem, M., McAuley, K.E., Sandy, D.J., Sorensen, T.L-M., Waterman, D., Johnson, L.N.
The Phase I MX Beam lines at Diamond Light Source.
AIP Conference Proceedings 1234, 165-168 (2010)

Drew, D., Klebsch, M.M., Newstead, S., Flaig, R., De Gier, J-W., Iwata, S., Beis, K.
The structure of the efflux pump AcrB in complex with bile acid.
Molecular Membrane Biology 25 677-682 (2008)
doi: 10.1080/09687680802552257

Greschik, H., Althage, M., Flaig, R., Sato, Y., Chavant, V., Peluso-Iltis, C., Choulier, L., Cronet, P., Rochel, N., Schüle, R., Strömstedt, P-E., Moras, D.
Communication between the ERR-alpha homodimer interface and the PGC-1-alpha
binding surface via the helix 8-9 loop.
J. Biol. Chem. 283 20220-20230 (2008)

Sorensen, T.L-M., McAuley, K.E., Flaig, R., Duke, E.H.M.
New light for science: synchrotron radiation in structural medicine.
Trends in Biotechnology 24(11) 500-508 (2006)
doi:10.1016/j.tibtech.2006.09.006

Flaig, R., Greschik, H., Peluso-Iltis, C., Moras, D.
Structural Basis for the Cell-specific Activities of the NGFI-B and the Nurr1 Ligand-binding Domain.
J. Biol. Chem. 280 19250-19258 (2005)
doi: 10.1074/jbc.M413175200

Kammerer, S., Germain, P., Flaig, R., Peluso-Iltis, C., Mitschler, A., Rochel, N., Gronemeyer, H., Moras, D.
RAR-beta ligand-binding domain bound to an SRC-1 co-activator peptide: purification, crystallization and preliminary X-ray diffraction analysis.
Acta Crystallogr. D60 2048-2050 (2004)

Greschik, H., Flaig, R., Renaud, J-P., Moras, D.
Structural basis for the Deactivation of the Estrogen-related Receptor gamma by Diethylstilbestrol or 4-Hydroxytamoxifen and Determinants of Selectivity
J. Biol. Chem. 279, 33639-33646 (2004)

Wagner, A., Flaig, R., Dittrich, B., Schmidt, H., Koritsanszky, T., Luger, P.
Charge Density and Electrostatic Potentials of two Penicillin Derivatives
Chem. Eur. J. 10, 2977-2982 (2004)

Wagner, A., Flaig, R., Zobel, D., Dittrich, B., Bombicz, P., Strumpel, M., Luger, P., Koritsanszky, T., Krane, H.G.
Structure and Charge Density of a C60-Fullerene Derivative Based on a High Resolution Synchrotron Diffraction Experiment at 100 K
J. Phys. Chem. A106, 6581-6590 (2002)

Kingsford-Adaboh, R., Dittrich, B., Wagner, A., Messerschmidt, M., Flaig, R., Luger, P.
Topological Analysis of D,L-Argininine Monohydrate at 100K
Z. Kristallogr. 217, 168-173 (2002)

Dittrich, B., Koritsanszky, T., Grosche, M., Scherer, W., Flaig, R., Wagner, A., Krane, H.G., Kessler, H., Riemer, C., Schreurs, A.M.M., Luger, P.
Reproducibility and Transferability of Topological Properties: Experimental Charge Density of the Hexapeptide cyclo-(D,L-Pro)2-(L-Ala)4 Monohydrate
Acta Crystallogr. B58, 721-727 (2002)

Flaig, R., Koritsanszky, T., Dittrich, B., Wagner, A., Luger, P.
Intra and Intermolecular Topological Properties of Amino Acids - A Comparative Study of Experimental and Theoretical Results
J. Am. Chem. Soc. 124, 3407-3417 (2002)

Flaig, R., Koritsanszky, T., Soyka, R., Häming, L., Luger, P.
Electronic Insight into an AntiThrombotic Agent by High-resolution X-ray Crystallography
Einblick in die elektronische Struktur eines antithrombotischen Wirkstoffs durch hochaufgelöste Röntgenbeugung
Angew. Chem. Int. Ed. 40, 355-359 (2001), Angew. Chem. 113, 368-371 (2001)

Dittrich, B., Flaig, R., Koritsanszky, T., Krane, H.G., Morgenroth, W., Luger, P.
Topological Properties of the Peptide Bond in Glycyl-L-threonine Dihydrate Based on a Fast Synchrotron/CCD-Diffraction Experiment at 100K
Chem. Eur. J. 6, 2582-2589 (2000)

Flaig, R., Koritsanszky, T., Janczak, J., Krane, H.G., Morgenroth, W., Luger, P.
Fast Experiments for Charge Density Determination: Topological Analysis and Electrostatic Potential of the Amino Acids L-Asn, DL-Glu, DL-Ser, and L-Thr
Schnelle Experimente zur Ladungsdichtebestimmung: topologische Analyse und elektrostatisches Potential der Aminosäuren L-Asn, DL-Glu, DL-Ser und L-Thr
Angew. Chem. Int. Ed. 38, 1397-1400 (1999), Angew. Chem. 111, 1494-1497 (1999)

Flaig, R., Koritsanszky, T., Zobel, D., Luger, P.
Topological Analysis of the Experimental Electron Densities of Amino Acids. 1. DL-Aspartic Acid at 20K
J. Am. Chem. Soc. 120, 2227-2238 (1998)

Koritsanszky, T., Flaig, R., Zobel, D., Krane, H.G., Morgenroth, W., Luger, P.
Accurate Experimental Electronic Properties of DL-Proline Monohydrate Obtained Within 1 Day
Science 279, 356-358 (1998)
 

Dissertation/Thesis

Neue experimentelle Methoden der Ladungsdichtebestimmung - New experimental methods of charge density determination, FU Berlin (Germany) (2000)

Biography - +

Biography

Ralf studied chemistry at the universities of Freiburg (Germany) and FU Berlin (Germany), and started using synchrotron radiation in 1996 as part of a diploma project in low temperature crystallography and charge density.

He obtained his Dr. rer. nat. degree from the FU Berlin in 2000. During his diploma and thesis in the group of Prof. Peter Luger, Ralf established new methods of experimental charge density determination which are now widely used in the field.

After a short Postdoc at the FU Berlin, doing experimental and theoretical investigations of intramolecular and intermolecular interactions of biologically relevant compounds, he moved to the Laboratoire de Biologie et Génomique Structurales at the IGBMC Strasbourg (France) in 2001. During his Postdoc in the group of Dr. Dino Moras he concentrated on structural studies of the ligand binding domain of nuclear receptors (NRs) involved in the nervous system and neurodegenerative diseases.  Ralf also investigated the isotype selectivity in nuclear receptors of the steroid receptor superfamily and performed structural studies of estrogen-related receptors bound to different ligands in collaboration with industrial partners.

In 2004 Ralf joined Diamond Light Source as a Beamline Scientist for the Macromolecular Crystallography beamlines. He established the operation of beamline I04 and contributed significantly to the commissioning of beamline I04-1. Ralf's current interest is the improvement of beamline instrumentation with a focus on multi-axis goniometry and diagnostic tools. He has also established a new collaboration in the structural biology of histone modification.

 

Awards

(2000) Prize for an outstanding Ph.D. thesis based on research at DESY, awarded by the Association of the Friends and Sponsors of DESY

Professional Body Memberships

Deutsche Gesellschaft für Kristallographie (DGK)
British Crystallographic Association (BCA)
The Biochemical Society