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PRESENTATION II NAME

PRESENTATION II NAME. Dihydrofolate Reductase Beta lactmase p300 Macrophage Infectivity Potentiator. By Christine Harvey. Dihydrofolate Reductase in Escherichia coli. Class: oxidoreductase Reduces dihydrofolate (DHF) to tetrahydrofolate (THF)

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PRESENTATION II NAME

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  1. PRESENTATION II NAME Dihydrofolate Reductase Beta lactmase p300 Macrophage Infectivity Potentiator By Christine Harvey

  2. Dihydrofolate Reductasein Escherichia coli

  3. Class: oxidoreductase • Reduces dihydrofolate (DHF) to tetrahydrofolate (THF) • THF is a precursor to amino acids, purine and thymidylate. • DHFR is imperative to cell life http://en.wikipedia.org/wiki/DHFR

  4. Function Source: Schweitzer, Barry I., et al. The FASEB Journal Vol 4, “Dihydrofolate reductase as a therapeutic target.” May 1990.

  5. Mechanism http://en.wikipedia.org/wiki/DHFR

  6. Structure

  7. Binding Pocket

  8. MOVIE

  9. Sequence Alignment

  10. Phylogenetic Tree

  11. Beta-Lactamasein Escherichia coli

  12. Class: Hydrolase • Beta Lactamase is produce by bacteria after being exposed to beta lactam antibiotics • Responsible for beta lactam antibiotic resistance

  13. Penicillin • Contains beta lactam ring

  14. Mechanism

  15. 21

  16. p300In Homo Sapiens

  17. Class: Transferase • p300 transfers an acetyl group from acetyl coenzyme A to an active site lysine • Transcriptional activation occurs upon acetyl transfer

  18. Title • p300 is responsible for cell growth before and after birth • Cancer suppressor

  19. Domains Taz2 KIX Bromodomain HAT Zinc Fingers (3) Taz2 Creb

  20. Histone Acetyl Transferase • Active site tyrosine acts as nucleophile Source: http://www.bmolchem.wisc.edu/labs/denu/images/hats/sequential.jpg

  21. Docking

  22. 39

  23. Macrophage Infectivity Potentiatorin Legionella pneumophila

  24. Legionella pneumophila • gram negative bacteria • Causes Legionnaires’ disease • Carried in aerosols from man-made water systems

  25. MIP • Class: Isomerase • Catalyzes the isomeration of the N-terminal on proline • Cause of virulence in Legionnaires’ disease • Located on outer membrane protein • 25 kDa

  26. Crystalization • Solution: 100 mM MES (pH 6.1–6.5), 15–20% (w/v) PEG 8000 and 500 mM zinc acetate. Protein concentration was 10 mg ml–1in 20 mM HEPES, pH 7.0 • Crystals were grown for 2-3 weeks at 288K • X-ray data was collected at 100K in a nitrogen gas stream (dried paraffin oil) at 2.4 Angstrom resolution • Multiwavelength anomalous dispersion (MAD) with zinc was used for phasing

  27. Source: Riboldi-Tunnicliffe, Alan et al., Nature Structural Biology, vol.8: 9. “Crystal structure of Mip, a prolylisomerase from Legionella pneumophila.” September 2001. 44

  28. Mechanism • Peptidyl-prolyl cis-trans isomerases’ (PPIases) mechanism is not currently know Source: Park, Steven T., et al. Journal of Biological Chemistry. Vol. 267 No.5, “PPIase Catalysis by Human Fk506-binding Protein Proceeds Through a Conformational Twist Mechanism.” February 1992.

  29. Source: Riboldi-Tunnicliffe, Alan et al., Nature Structural Biology, vol.8: 9. “Crystal structure of Mip, a prolylisomerase from Legionella pneumophila.” September 2001.

  30. 49

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