Neutron Scattering Scientist, IMAGINE and MaNDi diffractometers; Associate Professor, NCSU Biochemistry
Flora Meilleur is a structural biologist specializing in protein chemistry and neutron crystallography, and serves as an instrument scientist on the IMAGINE and MaNDI instruments (HFIR CG-4D and SNS BL-11B) at Oak Ridge National Laboratory (ORNL). Meilleur received her PhD in biophysics from the European Molecular Biology Laboratory (EMBL) and Université Grenoble Alpes (Grenoble, France) in 2004. After graduation, she served as instrument scientist on the LADI diffractometer at the Institut Laue Langevin (ILL). She joined ORNL in 2005 and has held a joint faculty appointment with the Biochemistry department of North Carolina State University since 2007. She is an associate professor since 2015. In 2009, Meilleur established a university consortium that secured NSF funding to build the IMAGINE instrument at HFIR. She served as lead scientist on IMAGINE 2009-2017, building, commissioning and delivering the instrument into the user program in 2013. She supports and collaborates with users to elucidate enzymatic mechanisms using neutron diffraction. Her own research focuses on cellulose degrading enzymes, including the recently discovered lytic polysaccharide monooxygenases. Graduate students and post-doctoral fellows working with her use small angle X-ray/neutron scattering, X-ray/neutron crystallography, DFT calculations and isotopic labeling techniques to study the structure, function and dynamics of these systems. She has co-organized and chaired neutron focused sessions at international meetings, and since 2010 has organized and led an annual workshop entitled Neutrons in Structural Biology at ORNL. She served as a member of the SNS/HFIR user committee (SHUG) from 2007 to 2009 and served two terms as a member-at-large of the NSSA between 2008 and 2012. Meilleur was appointed as a co-editor for Journal of Applied Crystallography in 2016 and recently elected by her peers as the new Secretary of the Neutron Scattering Society of America as of January 1, 2019.
2013 ORNL Significant Event Award (Team award; Role: Science lead)
We primarily use a combination of X-ray and neutron diffraction and scattering to probe enzyme structure, dynamics and function. Our goal is to map intra- and intermolecular interactions that govern enzyme function within the microenvironment of the catalytic site. Knowledge of local electrostatics, hydrogen-bonding networks and protonation states of titratable catalytic residues is essential for proper thermodynamic modeling and for predicting binding interactions in molecular recognition and catalysis.
We are interested in the enzymatic cellulose degradation, a key challenge remaining to be overcome for efficient industrial development of cellulose based products. Understanding how wood degrading organism enzymes function is required to guide enzyme engineering and design of more efficient enzymes. Two types of extracellular enzymatic systems have been identified in microorganisms capable of cellulose degradation: a hydrolytic system and an oxidative system. Our efforts are focused on gaining insight into the structures, dynamics and functions of enzymes from both systems.
We are also interested in understanding cytochrome P450s, one of nature's most versatile biologic catalysts. Cytochromes P450 (P450s) are ubiquitous enzymes catalyzing monooxygenation reactions and playing diverse functional roles in a broad range of biological systems. In mammals they are involved in a variety of biochemical processes including carcinogenesis, drug metabolism, biosynthesis of lipids and steroids or degradation of xenobiotics.
1. Meilleur F., Coates L., Cuneo M. J., Myles D.A.A. (2018) The Neutron Macromolecular Crystallography Instruments at Oak Ridge National Laboratory: Advances, Challenges and Opportunities. Crystals. In press.
2. Coates L., Cao H. B., Chakoumakos B. C., Frontzek M. D., Hoffmann C., Kovalevsky A. Y., Liu Y., Meilleur F., dos Santos A. M., Myles D. A. A., Wang X. P., Ye F. (2018) A suite-level review of the neutron single-crystal diffraction instruments at Oak Ridge National Laboratory. Rev. Sci. Instr. 89, 092802
3. Haberl B., Dissanayake S., Wu Y., Myles D. A. A., dos Santos A. M., Loguillo M.,
Rucker G. M., Armitage D. P., Cochran M., Andrews K. M., Hoffmann C., Cao H., Matsuda M., Meilleur F., Ye F., Molaison J. J., Boehler R. (2018) Next-generation diamond cell and applications to single-crystal neutron diffraction. Rev. Sci. Instr. 89, 092902
4. Duff M. R., Borreguero J. M., Cuneo M., Ramanathan A., He J., Kamath G., Chennubhotla C. S., Meilleur F., Howell E. E, Herwig K. W., Myles D. A. A., Agarwal P. K. (2018) Modulating enzyme activity by altering protein dynamics with solvent. Biochemistry 57:4263-4275
5. G. C. Schroder, W. B. O'Dell, D. A. A. Myles, A. Kovalevsky, F. Meilleur. (2018) IMAGINE: neutrons reveal enzyme chemistry. Acta Cryst. D74:778-786
6. A. M. Bodenheimer, W. B. O’Dell, C. B. Stanley, R. C. Oliver, S. Qian, F. Meilleur. (2018) Structural investigation of Cellobiose Dehydrogenase IIA: Insights from Small Angle Scattering into Intra- and Intermolecular Electron Transfer Mechanisms. Biochem Biophys Acta. 1862:1031-1039
7. Li L., Shukla S., Meilleur F., Standaert R.F., Pierce J., Myles D.A., Cuneo M.J. (2017) Neutron crystallographic studies of T4 lysozyme at cryogenic temperature. Protein Sci. 26: 2098-2104
8. Hiromoto T., Meilleur F., Shimizu R., Shibazaki C., Adachi M., Tamada T., Kuroki R. (2017) Neutron structure of the T26H mutant of T4 phage lysozyme provides insight into the catalytic activity of the mutant enzyme and how it differs from that of wild type. Protein Sci. 26: 1953-1963
9. Bodenheimer A.M., O’Dell W.B., Stanley C.B., Meilleur F. (2017) Structural studies of Neurospora crassa LPMO9D and redox partner CDHIIA using neutron crystallography and small-angle scattering. Carbohydr. Res. 448:200-204
10. O’Dell W.B., Swartz P., Weiss K., Meilleur F. (2017) Crystallization of a fungal lytic polysaccharide monooxygenase expressed from glycoengineered Pichia pastoris for X-ray and neutron diffraction Acta Cryst. F73:70-78
11. Golden E., Duff A.P., Karton A., Blakeley M.P., Meilleur F., Vrielink A. (2017) An extended N-H bond driven by a conserved second order interaction orients the flavin N5 orbital in cholesterol oxidase. Scientific Reports 7, Article Number 40517
12. O’Dell W. B., Aggarwal P., Meilleur F. (2017) Oxygen Activation at the Active Site of a Fungal Lytic Polysaccharide Monooxygenase. Angew. Chem. Int. Ed. 56:767-770
13. Bodenheimer A. M., Meilleur F. (2016) Crystal structures of wild-type Trichoderma reesei Cel7A catalytic domain in open and closed states. FEBS Letters 590:4429-4438
14. O’Dell W.B., Bodenheimer A.M., Meilleur F. (2016) Neutron protein crystallography: insight into enzyme chemistry. Arch Biochem. Biophys. 602:48-60
15. Zhao J.K., Pierce J., Myles D.A., Robertson J.L., Herwig K.W., Standaert R., Cuneo M., Li L., Meilleur F. (2016) Dynamically polarized samples for neutron protein crystallography at the Spallation Neutron Source. DOI: 10.1088/1742-6596/746/1/012008