PAOBMB Plenary Lecture
July 4th, Monday, 08.30-09.20
Natalie C.J. Strynadka

natalie@byron.biochem.ubc.ca
http://www.biochem.ubc.ca/Faculty/Strynadka.html
http://www.hhmi.org/grants/awards/indiv/scholars/stry.html
CV
Dr. Strynadka received her Ph.D. in structural biology from the University of Alberta in 1990, where she subsequently conducted postdoctoral research in the Departments of Biochemistry and Microbiology until being given the position of Research Fellow in 1995. In 1997 she achieved her current position of Assistant Professor of the Department of Biochemistry of the University of British Columbia in Vancouver, Canada. In 1997 she received the honor of being named a Medical Research Council of Canada Scholar. In 1998 she received the CFI New Opportunitues Award, and in 1999 was named a Burroughs Wellcome New Investigator in the Pharmacological Sciences. Her HHMI project involves structural characterization of bacterial membrane components with the goal of discovering new antibiotic targets.
Research Interest
Structure-based antibiotic discovery on the bacterial cell membrane

Bacterial resistance to standard antibiotic therapies is rapidly becoming a critical health problem worldwide. In the past several years, the frequency and spectrum of antimicrobial-resistant infections have increased in hospitals and in the community. Certain infections that are essentially untreatable have begun to occur as epidemics both in developing nations and in institutional settings around the globe. We are using the techniques of molecular biology, x-ray crystallography, and computational molecular modeling/docking to study bacterial proteins that, because of their essential role in bacterial viability, are logical candidates for novel antibiotic design. The systems chosen reside on or within the bacterial cell membrane: the beta lactam-resistant cell-wall transpeptidase MecA from the antibiotic-resistant "superbugs" Streptococcus pneumoniae and Staphylococcus aureus; the beta-lactam efflux pump MexA,B-OprM from the opportunistic clinical pathogen Pseudomonas aeruginosa; and the bacterial signal peptidases and other components of the Sec-dependent and type III bacterial secretion systems. It is proposed that localization of these proteins on the outer surface of the bacterial membrane will allow for maximal accessibility to the designed antibiotics. Recent progress from our laboratory in elucidating the structure, mechanism of action, and potential modes of inhibition of these systems is discussed.

Selected recent publications
  1. Chiu, C.P., Watts, A.G., Lairson, L.L., Gilbert, M., Lim, D., Wakarchuk, W.W., Withers, S.G. and Strynadka, N.C. (2004)
    Structural analysis of the sialyltransferase CstII from Campylobacter jejuni in complex with a substrate analog.
    Nature Struct. Mol. Biol. 11, 163-170.
  2. Bertero, M.G., Rothery, R.A., Palak, M., Hou, C., Lim, D., Blasco, F., Weiner, J.H. and Strynadka, N.C. (2003)
    Insights into the respiratory electron transfer pathway from the structure of nitrate reductase A.
    Nature Struct. Biol. 10, 681-687.
  3. Lim, D. and Strynadka, N.C. (2002)
    Structural basis for the beta lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus. Nature Struct Biol. 9, 870-876.
  4. Luo, Y., Bertero, M.G., Frey, E.A., Pfuetzner, R.A., Wenk, M.R., Creagh, L., Marcus, S.L., Lim, D., Sicheri, F., Kay, C., Haynes, C., Finlay, B.B. and Strynadka, N.C. (2001)
    Structural and biochemical characterization of the type III secretion chaperones CesT and SigE.
    Nature Struct Biol. 8, 1031-1036.
  5. Lim, D., Park, H.U., De Castro, L., Kang, S.G., Lee, H.S., Jensen, S., Lee, K.J. and Strynadka, N.C. (2001)
    Crystal structure and kinetic analysis of beta-lactamase inhibitor protein-II in complex with TEM-1 beta-lactamase.
    Nat Struct Biol. 8, 848-852.
  6. Luo, Y., Pfuetzner, R.A., Mosimann, S., Paetzel, M., Frey, E.A., Cherney, M., Kim, B., Little, J.W. and Strynadka, N.C. (2001)
    Crystal structure of LexA: a conformational switch for regulation of self-cleavage.
    Cell 106, 585-694.
  7. Persson, K., Ly, H.D., Dieckelmann, M., Wakarchuk, W., Withers, S.G. and Strynadka, N.C. (2001)
    Crystal structure of the retaining galactosyltransferase LgtC from Neisseria mentingitidis in complex with donor and acceptor sugar analogs.
    Nature Struct. Biol. 8, 166-175.