Udo Oppermann

University of Oxford, Oxford, England, United Kingdom

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Publications (193)1050.22 Total impact

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    ABSTRACT: Farnesyl pyrophosphate synthase (FPPS) is the major molecular target of nitrogen-containing bisphosphonates (N-BPs), used clinically as bone resorption inhibitors. We investigated the role of threonine 201 (Thr201) and tyrosine 204 (Tyr204) residues in substrate binding, catalysis and inhibition by N-BPs, employing kinetic and crystallographic studies of mutated FPPS proteins. Mutants of Thr201 illustrated the importance of the methyl group in aiding the formation of the Isopentenyl pyrophosphate (IPP) binding site, while Tyr204 mutations revealed the unknown role of this residue in both catalysis and IPP binding. The interaction between Thr201 and the side chain nitrogen of N-BP was shown to be important for tight binding inhibition by zoledronate (ZOL) and risedronate (RIS), although RIS was also still capable of interacting with the main-chain carbonyl of Lys200. The interaction of RIS with the phenyl ring of Tyr204 proved essential for the maintenance of the isomerized enzyme-inhibitor complex. Studies with conformationally restricted analogues of RIS reaffirmed the importance of Thr201 in the formation of hydrogen bonds with N-BPs. In conclusion we have identified new features of FPPS inhibition by N-BPs and revealed unknown roles of the active site residues in catalysis and substrate binding. Copyright © 2015. Published by Elsevier Inc.
    Bone 08/2015; DOI:10.1016/j.bone.2015.08.020 · 3.97 Impact Factor
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    Adam Cribbs · Marc Feldmann · Udo Oppermann
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    ABSTRACT: The term 'epigenetics' loosely describes DNA-templated processes leading to heritable changes in gene activity and expression, which are independent of the underlying DNA sequence. Epigenetic mechanisms comprise of post-translational modifications of chromatin, methylation of DNA, nucleosome positioning as well as expression of noncoding RNAs. Major advances in understanding the role of DNA methylation in regulating chromatin functions have been made over the past decade, and point to a role of this epigenetic mechanism in human disease. Rheumatoid arthritis (RA) is an autoimmune disorder where altered DNA methylation patterns have been identified in a number of different disease-relevant cell types. However, the contribution of DNA methylation changes to RA disease pathogenesis is at present poorly understood and in need of further investigation. Here we review the current knowledge regarding the role of DNA methylation in rheumatoid arthritis and indicate its potential therapeutic implications.
    Therapeutic advances in musculoskeletal disease 08/2015; 7(5). DOI:10.1177/1759720X15598307
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    ABSTRACT: Aldehyde dehydrogenases (ALDHs) metabolize reactive aldehydes and possess important physiological and toxicological functions in areas such as CNS, metabolic disorders, and cancers. Increased ALDH (e.g., ALDH1A1) gene expression and catalytic activity are vital biomarkers in a number of malignancies and cancer stem cells, highlighting the need for the identification and development of small molecule ALDH inhibitors. A new series of theophylline-based analogs as potent ALDH1A1 inhibitors is described. The optimization of hits identified from a quantitative high throughput screening (qHTS) campaign led to analogs with improved potency and early ADME properties. This chemotype exhibits highly selective inhibition against ALDH1A1 over ALDH3A1, ALDH1B1, and ALDH2 isozymes as well as other dehydrogenases such as HPGD and HSD17β4. Moreover, the pharmacokinetic evaluation of selected analog 64 (NCT-501) is also highlighted.
    Journal of Medicinal Chemistry 07/2015; 58(15). DOI:10.1021/acs.jmedchem.5b00577 · 5.45 Impact Factor
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    ABSTRACT: The Structural Genomics Consortium (SGC) and its clinical, industry and disease-foundation partners are launching open-source preclinical translational medicine studies.
    Nature Reviews Drug Discovery 03/2015; 14(3):149-50. DOI:10.1038/nrd4565 · 41.91 Impact Factor
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    ABSTRACT: Dentine matrix protein 1 (DMP-1) is a non-collagenous matrix protein found in dentine and bone. It is highly expressed by osteocytes and has been identified in primary benign and malignant osteogenic bone tumours. Bone formation and matrix mineralisation are seen in a variety of benign and malignant soft tissue tumours and tumour-like lesions, and in this study, we analysed immunohistochemically the DMP-1 expression in a wide range of soft tissue lesions (n = 254) in order to assess whether DMP-1 expression is useful in the histological diagnosis of soft tissue tumours. Matrix staining of DMP-1 was seen in all cases of myositis ossificans, fibro-osseous tumour of the digits, extraskeletal soft tissue osteosarcoma and in most cases of ossifying fibromyxoid tumour. DMP-1 was also noted in dense collagenous connective tissue of mineralising soft tissue lesions such as tumoural calcinosis, dermatomyositis and calcific tendinitis. DMP-1 was expressed in areas of focal ossification and calcification in synovial sarcoma and other soft tissue tumours. With few exceptions, DMP-1 was not expressed in other benign and malignant soft tissue tumours. Our findings indicate that DMP-1 is a matrix marker of bone formation and mineralisation in soft tissue tumours. DMP-1 expression should be particularly useful in distinguishing extraskeletal osteosarcoma and ossifying fibromyxoid tumour from other sarcomas and in identifying areas of osteoid/bone formation and mineralisation in soft tissue tumours.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 01/2015; DOI:10.1007/s00428-014-1706-3 · 2.65 Impact Factor
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    ABSTRACT: Prostaglandins (PGs) are lipid compounds derived from arachidonic acid by the action of cyclooxygenases, acting locally as messenger molecules in a wide variety of physiological processes, such as inflammation, cell survival, apoptosis, smooth muscle contraction, adipocyte differentiation, vasodilation and platelet aggregation inhibition. In the inactivating pathway of PGs, the first metabolic intermediates are 15-keto-PGs, which are further converted into 13,14-dihydro-15-keto-PGs by different enzymes having 15-keto-PG reductase activity. Three human PG reductases (PGR), zinc-independent members of the medium-chain dehydrogenase/reductase (MDR) superfamily, perform the first irreversible step of the degradation pathway. We have focused on the characterization of the recombinant human enzyme prostaglandin reductase 1 (PGR1), also known as leukotriene B4 dehydrogenase. Only a partial characterization of this enzyme, isolated from human placenta, had been previously reported. In the present work, we have developed a new HPLC-based method for the determination of the 15-keto-PG reductase activity. We have performed an extensive kinetic characterization of PGR1, which catalyzes the NADPH-dependent reduction of α,β-double bond of aliphatic and aromatic aldehydes and ketones, and 15-keto-PGs. PGR1 also shows low activity in the oxidation of leukotriene B4. The best substrates in terms of kcat/Km were 15-keto-PGE2, trans-3-nonen-2-one and trans-2-decenal. Molecular docking simulations, based on the three-dimensional structure of the human enzyme (PDB ID 2Y05), and site-directed mutagenesis studies were performed to pinpoint important structural determinants, highlighting the role of Arg56 and Tyr245 in 15-keto-PG binding. Finally, inhibition analysis was done using non-steroidal anti-inflammatory drugs (NSAIDs) as potential inhibitors. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Chemico-Biological Interactions 01/2015; 234. DOI:10.1016/j.cbi.2015.01.021 · 2.58 Impact Factor
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    ABSTRACT: Short-chain dehydrogenases/reductases (SDRs) constitute a large, functionally diverse branch of enzymes within the class of NAD(P)(H) dependent oxidoreductases. In humans, over 80 genes have been identified with distinct metabolic roles in carbohydrate, amino acid, lipid, retinoid and steroid hormone metabolism, frequently associated with inherited genetic defects. Besides metabolic functions, a subset of atypical SDR proteins appears to play critical roles in adapting to redox status or RNA processing, and thereby controlling metabolic pathways.
    Chemico-Biological Interactions 12/2014; 234. DOI:10.1016/j.cbi.2014.12.013 · 2.58 Impact Factor
  • X Cheng · E S Hookway · T Kashima · U Oppermann · A Galione · N A Athanasou
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    ABSTRACT: Osteoclasts are specialised bone resorbing cells which form by fusion of circulating mononuclear phagocyte precursors. Bone resorption results in the release of large amounts of calcium into the extracellular fluid (ECF), but it is not certain whether changes in extracellular calcium concentration [Ca(2+)]e influence osteoclast formation and resorption. In this study, we sought to determine the effect of [Ca(2+)]e and NAADP, a potent calcium mobilising messenger that induces calcium uptake, on human osteoclast formation and resorption. CD14+ human monocytes were cultured with M-CSF and RANKL in the presence of different concentrations of calcium and NAADP and the effect on osteoclast formation and resorption evaluated. We found that the number of TRAP+ multinucleated cells and the extent of lacunar resorption were reduced when there was an increase in extracellular calcium and NAADP. This was associated with a decrease in RANK mRNA expression by CD14+ cells. At high concentrations (20 mM) of [Ca(2+)]e mature osteoclast resorption activity remained unaltered relative to control cultures. Our findings indicate that osteoclast formation is inhibited by a rise in [Ca(2+)]e and that RANK expression by mononuclear phagocyte osteoclast precursors is also [Ca(2+)]e dependent. Changes in NAADP also influence osteoclast formation, suggesting a role for this molecule in calcium handling. Osteoclasts remained capable of lacunar resorption, even at high ECF [Ca(2+)]e, in keeping with their role in physiological and pathological bone resorption.
    Calcified Tissue International 11/2014; 96(1). DOI:10.1007/s00223-014-9939-3 · 3.27 Impact Factor
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    ABSTRACT: Replying to B. Heinemann . Nature 514, http://dx.doi.org/10.1038/nature13688 (2014)We welcome the accompanying Comment by Heinemann et al., in which the authors use an extensive panel of sensitive KDM assays to independently confirm our results that GSK-J1 is a potent KDM6 inhibitor. Additionally, Heinemann et al. demonstrate that GSK-J1 has some, albeit weaker, activity towards KDM5B and KDM5C, for which we only had preliminary data available at the time of our original publication. As our jumonji assay portfolio expands, we have continued to update the GSK-J1 activity profile on the SGC website (http://www.thesgc.org/chemical-probes/GSKJ1); this includes KDM5 inhibition activity by GSK-J1 similar to that reported by Heinemann. In conclusion, GSK-J1 remains the most selective KDM inhibitor yet disclosed and thus a valuable chemical tool.
    Nature 10/2014; 514(7520):E2. DOI:10.1038/nature13689 · 41.46 Impact Factor
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    ABSTRACT: The retinoblastoma tumor suppressor protein pRb is a key regulator of cell cycle progression and mediator of the DNA damage response. Lysine methylation at K810, which occurs within a critical Cdk phosphorylation motif, holds pRb in the hypophosphorylated growth-suppressing state. We show here that methyl K810 is read by the tandem tudor domain containing tumor protein p53 binding protein 1 (53BP1). Structural elucidation of 53BP1 in complex with a methylated K810 pRb peptide emphasized the role of the 53BP1 tandem tudor domain in recognition of the methylated lysine and surrounding residues. Significantly, binding of 53BP1 to methyl K810 occurs on E2 promoter binding factor target genes and allows pRb activity to be effectively integrated with the DNA damage response. Our results widen the repertoire of cellular targets for 53BP1 and suggest a previously unidentified role for 53BP1 in regulating pRb tumor suppressor activity.
    Proceedings of the National Academy of Sciences 07/2014; 111(31). DOI:10.1073/pnas.1403737111 · 9.67 Impact Factor
  • K. Rooke · L. Kruidenier · H. Che · P. Mander · C. Swales · R. Prinjha · U. Oppermann
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    ABSTRACT: Background Macrophages are central players in the pathogenesis of rheumatoid arthritis, and targeted inhibition of their principal cytokine products, TNFα and IL-6, are effective treatments. However, a significant proportion of patients still fail to respond to current therapies, and there is a continuing need for new therapeutic targets. Epigenetic modifications are increasingly recognised as key pathogenic features of RA and therefore inhibition of epigenetic anomalies has been identified as a potential future therapeutic strategy. Objectives This study used small molecule inhibitors to identify epigenetic factors that mediate macrophage-derived pro-inflammatory cytokine production from healthy donors and patients with RA. Methods Peripheral blood monocytes (PBMCs) were isolated from 10 healthy donors and 3 patients with rheumatoid arthritis; synovial fluid (SF) macrophages were also derived from the RA patients following therapeutic arthrocentesis. All patients were recruited from the Nuffield Orthopaedic Centre and gave written informed consent. PBMCs were differentiated into macrophages and stimulated with lipopolysaccharide (LPS) as a model of inflammation. PBMC and SF-derived macrophages were then treated with a panel of small molecule bromodomain, demethylase and deacetylase inhibitors to assess the impact of chromatin modification on macrophage pro-inflammatory cytokine production, including TNFα and IL-6. Cytokine production was detected by multiplex ELISA and supported by q-PCR data. Cell viability was determined using a WST-1 assay. Results Macrophages from healthy volunteers and patients with RA responded differently to the tested epigenetic inhibitors. Bromodomain (PFI-1, (+)-JQ1 and I-BET), demethylase (GSK-J4) and deacetylase (SAHA and CXD101) inhibitors all significantly reduced the production of TNFα and IL-6 from healthy donor PBMC-derived macrophages. The bromodomain and demethylase inhibitors effectively inhibited cytokine production from the PBMCs of patients with RA, but of the deacetylase inhibitors tested, only SAHA had significant effect. In addition, cytokine production from RA SF-derived macrophages was significantly reduced by the bromodomain inhibitors and SAHA-mediated deacetylase inhibition, but there was no significant effect with demethylase inhibition. Conclusions Differential responses to epigenetic inhibitors may represent differences in epigenetic modifications or mechanisms between healthy and RA macrophages. Further investigation into these differences, as well as specific mechanistic effects of epigenetic inhibitors, could lead to a clearer understanding of disease pathogenesis and help to identify novel therapeutic targets. Acknowledgements This work was generously funded by BBSRC and GSK Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4218
    Annals of the Rheumatic Diseases 06/2014; 73(Suppl 2):823-824. DOI:10.1136/annrheumdis-2014-eular.4218 · 10.38 Impact Factor
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    ABSTRACT: 2-Oxoglutarate (2OG)-dependent oxygenases have important roles in the regulation of gene expression via demethylation of N-methylated chromatin components and in the hydroxylation of transcription factors and splicing factor proteins. Recently, 2OG-dependent oxygenases that catalyse hydroxylation of transfer RNA and ribosomal proteins have been shown to be important in translation relating to cellular growth, TH17-cell differentiation and translational accuracy. The finding that ribosomal oxygenases (ROXs) occur in organisms ranging from prokaryotes to humans raises questions as to their structural and evolutionary relationships. In Escherichia coli, YcfD catalyses arginine hydroxylation in the ribosomal protein L16; in humans, MYC-induced nuclear antigen (MINA53; also known as MINA) and nucleolar protein 66 (NO66) catalyse histidine hydroxylation in the ribosomal proteins RPL27A and RPL8, respectively. The functional assignments of ROXs open therapeutic possibilities via either ROX inhibition or targeting of differentially modified ribosomes. Despite differences in the residue and protein selectivities of prokaryotic and eukaryotic ROXs, comparison of the crystal structures of E. coli YcfD and Rhodothermus marinus YcfD with those of human MINA53 and NO66 reveals highly conserved folds and novel dimerization modes defining a new structural subfamily of 2OG-dependent oxygenases. ROX structures with and without their substrates support their functional assignments as hydroxylases but not demethylases, and reveal how the subfamily has evolved to catalyse the hydroxylation of different residue side chains of ribosomal proteins. Comparison of ROX crystal structures with those of other JmjC-domain-containing hydroxylases, including the hypoxia-inducible factor asparaginyl hydroxylase FIH and histone N(ε)-methyl lysine demethylases, identifies branch points in 2OG-dependent oxygenase evolution and distinguishes between JmjC-containing hydroxylases and demethylases catalysing modifications of translational and transcriptional machinery. The structures reveal that new protein hydroxylation activities can evolve by changing the coordination position from which the iron-bound substrate-oxidizing species reacts. This coordination flexibility has probably contributed to the evolution of the wide range of reactions catalysed by oxygenases.
    Nature 05/2014; 510(7505). DOI:10.1038/nature13263 · 41.46 Impact Factor
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    ABSTRACT: The Jumonji C lysine demethylases (KDMs) are 2-oxoglutarate- and Fe(II)-dependent oxygenases. KDM6A (UTX) and KDM6B (JMJD3) are KDM6 subfamily members that catalyze demethylation of Nϵ-methylated histone 3 lysine 27 (H3K27), a mark important for transcriptional repression. Despite reports stating that UTY(KDM6C) is inactive as a KDM, we demonstrate by biochemical studies, employing MS and NMR, that UTY(KDM6C) is an active KDM. Crystallographic analyses reveal that the UTY(KDM6C) active site is highly conserved with those of KDM6B and KDM6A. UTY(KDM6C) catalyzes demethylation of H3K27 peptides in vitro, analogously to KDM6B and KDM6A, but with reduced activity, due to point substitutions involved in substrate binding. The results expand the set of human KDMs and will be of use in developing selective KDM inhibitors.
    Journal of Biological Chemistry 05/2014; 289(26). DOI:10.1074/jbc.M114.555052 · 4.57 Impact Factor
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    S. J. B. Snelling · A. Kramm · C. Yapp · A. J. Carr · U. Oppermann
    Osteoarthritis and Cartilage 04/2014; 22:S141. DOI:10.1016/j.joca.2014.02.260 · 4.17 Impact Factor
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    ABSTRACT: The iron- and 2-oxoglutarate-dependent oxygenases constitute a phylogenetically conserved class of enzymes that catalyze hydroxylation reactions in humans by acting on various types of substrates, including metabolic intermediates, amino acid residues in different proteins and various types of nucleic acids. The discovery of jumonji (Jmj), the founding member of a class of Jmj-type chromatin modifying enzymes and transcriptional regulators, has culminated in the discovery of several branches of histone lysine demethylases, with essential functions in regulating the epigenetic landscape of the chromatin environment. This work has now been considerably expanded into other aspects of epigenetic biology and includes the discovery of enzymatic steps required for methyl-cytosine demethylation as well as modification of RNA and ribosomal proteins. This overview aims to summarize the current knowledge on the human Jmj-type enzymes and their involvement in human pathological processes, including development, cancer, inflammation and metabolic diseases.
    Epigenomics 02/2014; 6(1):89-120. DOI:10.2217/epi.13.79 · 4.65 Impact Factor
  • A. Kramm · S. Kubicek · J. E. Dunford · U. Oppermann
    Spring Meeting of the British-Society-for-Matrix-Biology; 10/2013
  • K. Rooke · L. Kruidenier · K. Che · P. Mander · C. Swales · R. Prinjha · U. Oppermann
    Spring Meeting of the British-Society-for-Matrix-Biology; 10/2013
  • S Munro · U Oppermann · N B La Thangue
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    ABSTRACT: Transcription factor E2F-1 and its interaction with pRb provide a key point of control in cell proliferation. E2F-1 participates in both cell cycle progression and apoptosis, and in cells exists with a DP dimerization partner protein, the most prominent being DP-1. By mining the tumor tissue and cancer cell line encyclopedia genomic databases, we identified the first somatic mutations in the DP-1 gene and describe 53 distinct mutation events here. The mutations are mostly missense mutations, but also include nonsense and frame-shift mutations that result in truncated DP-1 derivatives. Mutation occurs throughout the DP-1 gene but generally leaves protein dimerization activity intact. This allows the mutant derivatives to affect the properties of the E2F-1/DP-1 heterodimer through a transdominant mechanism, which changes the DNA binding, transcriptional activation and pRb-binding properties of the heterodimer. In particular, many DP-1 mutants were found to impair E2F-1-dependent apoptosis. Our results establish that somatic mutations in DP-1 uncouple normal control of the E2F pathway, and thus define a new mechanism that could contribute to aberrant proliferation in tumor cells.Oncogene advance online publication, 12 August 2013; doi:10.1038/onc.2013.316.
    Oncogene 08/2013; 33(27). DOI:10.1038/onc.2013.316 · 8.46 Impact Factor
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    ABSTRACT: Malonyl-coenzyme A decarboxylase (MCD) is found from bacteria to humans, has important roles in regulating fatty acid metabolism and food intake, and is an attractive target for drug discovery. We report here four crystal structures of MCD from human, Rhodopseudomonas palustris, Agrobacterium vitis, and Cupriavidus metallidurans at up to 2.3 Å resolution. The MCD monomer contains an N-terminal helical domain involved in oligomerization and a C-terminal catalytic domain. The four structures exhibit substantial differences in the organization of the helical domains and, consequently, the oligomeric states and intersubunit interfaces. Unexpectedly, the MCD catalytic domain is structurally homologous to those of the GCN5-related N-acetyltransferase superfamily, especially the curacin A polyketide synthase catalytic module, with a conserved His-Ser/Thr dyad important for catalysis. Our structures, along with mutagenesis and kinetic studies, provide a molecular basis for understanding pathogenic mutations and catalysis, as well as a template for structure-based drug design.
    Structure 06/2013; 21(7). DOI:10.1016/j.str.2013.05.001 · 5.62 Impact Factor
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    ABSTRACT: ah 2-Oxoglutarate and iron dependent oxygenases are therapeutic targets for human diseases. Using a representative 2OG oxygenase panel, we compare the inhibitory activities of 5-carboxy-8-hydroxyquinoline (IOX1) and 4-carboxy-8-hydroxyquinoline (4C8HQ) with that of two other commonly used 2OG oxygenase inhibitors, N-oxalylglycine (NOG) and 2,4-pyridinedicarboxylic acid (2,4-PDCA). The results reveal that IOX1 has a broad spectrum of activity, as demonstrated by the inhibition of transcription factor hydroxylases, representatives of all 2OG dependent histone demethylase subfamilies, nucleic acid demethylases and g-butyrobetaine hydroxylase. Cellular assays show that, unlike NOG and 2,4-PDCA, IOX1 is active against both cytosolic and nuclear 2OG oxygenases without ester derivatisation. Unexpectedly, crystallographic studies on these oxygenases demonstrate that IOX1, but not 4C8HQ, can cause translocation of the active site metal, revealing a rare example of protein ligand-induced metal movement.
    Chemical Science 06/2013; 4(8):3110-3117. DOI:10.1039/c3sc51122g · 9.21 Impact Factor

Publication Stats

7k Citations
1,050.22 Total Impact Points


  • 2005–2015
    • University of Oxford
      • Structural Genomics Consortium (SGC)
      Oxford, England, United Kingdom
  • 2008–2014
    • NIHR Oxford Biomedical Research
      Oxford, England, United Kingdom
  • 2011
    • University of Bristol
      • School of Biochemistry
      Bristol, England, United Kingdom
  • 2010
    • University of Toronto
      • Structural Genomics Consortium
      Toronto, Ontario, Canada
    • The University of Sheffield
      Sheffield, England, United Kingdom
  • 1996–2008
    • Karolinska Institutet
      • Department of Medical Biochemistry and Biophysics
      Solna, Stockholm, Sweden
  • 1992–1993
    • Philipps University of Marburg
      • Institute for Physiological Chemistry
      Marburg, Hesse, Germany