Petsko/Ringe Lab Research

1. Biodefense: Control of Virulence Structural Neurology: Alzheimer’s, Parkinson’s Enzyme and Pathway Evolution Structural Enzymology The Quiescent State Structural Oncology Petsko/Ringe Lab Research http://www.rose.brandeis.edu/PRLab/main.html

2. Petsko/Ringe Lab Research http://www.rose.brandeis.edu/PRLab/main.html

3. The Quiescent State Structural Oncology Research Areas Biodefense: Control of Virulence Structural Neurology: Alzheimer’s, Parkinson’s Enzyme and Pathway Evolution Structural Enzymology

4. Structural Enzymology

5. Protein Structure Determination by X-ray Crystallography

6. A Structural Approach to How Enzymes Work Control of Cofactor Chemistry PLP Enzymes Bridged Bimetalloenzymes H, H+, and H- Transfer Catalysis Proteases The Role of Enzyme Dynamics in Catalysis

7. E-S Complex of Mutarotase at 1.4Å Resolution

8. How Mutarotase Works

9. Ultra High Resolution

10. Ultra High Resolution: TYR 212 AT 4.3 

11. Atoms Can Be Identified From Their Electron Density Heights

12. Hydrogens on Ile 26

13. Bonding Electron Density?

14. The Quiescent State Structural Oncology Research Areas Biodefense: Control of Virulence Structural Neurology: Alzheimer’s, Parkinson’s Enzyme and Pathway Evolution Structural Enzymology

16. What have we done? Virulence genes Virulence genes 4. Development of new validated target for repression of virulence gene expression

17. DtxR: A Master Regulator of Bacterial Virulence

18. In Silico Drug Discovery

19. Sample DtxR Docking Result

20. Dagmar Ringe

21. The Quiescent State Structural Oncology Research Areas Biodefense: Control of Virulence Structural Neurology: Alzheimer’s, Parkinson’s Enzyme and Pathway Evolution Structural Enzymology

22. Evolution Darwin, C. On The Origin of Species (1859)

23. The LactonitrilePathway The Mandelonitrile Pathway

24. Structural Oncology Research Areas The Quiescent State Biodefense: Control of Virulence Structural Neurology: Alzheimer’s, Parkinson’s Enzyme and Pathway Evolution Structural Enzymology

25. G0: Life in Suspension

26. Networks of Genes Involved in G0

27. The Quiescent State Structural Oncology Research Areas Biodefense: Control of Virulence Structural Neurology: Alzheimer’s, Parkinson’s Enzyme and Pathway Evolution Structural Enzymology

28. The Anatomy of Neurodegeneration

29. Neurodegenerative Diseases • Alzheimer’s Disease (AD) - 4 million affected in U.S. • Parkinson’s Disease (PD) - 1.5 million affected • Amyotropic Lateral Sclerosis (ALS; Lou Gehrig’s Disease) - 20,000 affected • Tauopathies:Pick’s Disease; Frontotemporal Dementia with Parkinson’s Linked To Chromosome 17 (FTDP-17); Progressive Supranuclear Palsy (PSP); ALS/Parkinson’s with Dementia of Guam (Lytico-Bodig); Corticobasal Degeneration (CBD); Postencephalitic Parkinsonism (PCP) - >20,000 affected • Trinucleotide (CAG) Repeat Diseases (Polyglutamine Diseases):Huntington’s Disease; Spinocerebellar Ataxia 1 (SCA1);Machado-Joseph Disease; Kennedy’s Disease - 30,000 affected • Prion Diseases:Scrapie; Bovine Spongeoform Encephalitis (Mad Cow Disease); New Variant Creutzfeldt-Jacob Disease (NVCJD) - 400 affected

30. Department of Neurology, Harvard Medical School and the Brigham & Women’s Hospital, Boston, MA Center for Neurologic Diseases (Dennis Selkoe, Dir.) Laboratory for Drug Discovery for Neurodegeneration (Peter Lansbury, Dir.) Screening and Synthesis Lab (Ross Stein, Dir.) Structural Neurology Lab (Greg Petsko & Dagmar Ringe, Dirs.)

31. Structural Neurology

32. Gaucher Disease Gaucher Disease is an inborn error of metabolism. Although there are at least 34 mutations known to cause Gaucher Disease, there are 4 genetic mutations which account for 95% of the Gaucher Disease in the Ashkenazi Jewish population, and 50% of the Gaucher Disease in the general population. These can be identified through a blood test. The carrier rate for the mutations which cause Gaucher Disease may be as high as 1 in 14 among Jewish people of Eastern European ancestry, and 1 in 100 of the general population. Gaucher Disease is transmitted as an autosomal recessive; that is, it occurs equally among males and females, and both parents must carry the mutation for the child to have the disease. If both parents are carriers, then there is a 1 in 4 chance that the child will have Gaucher Disease, a 1 in 2 chance that the child will not have the disease but will be a carrier, and a 1 in 4 chance that the child will neither have the disease nor be a carrier.

33. People who are homozygous for loss-of-function mutations in the enzyme glucocerebrosidase have Gaucher Disease. The heterozygotes, the carriers, do not develop Gaucher Disease. They have a 300% increased risk of developing Parkinson’s Disease.

34. Glucocerebrosidase

35. The Glucocerebrosidase Reaction Isofagomine (AT2101), IC50=nM

36. Glucocerebrosidase + Gaucher Drug (Amicus Therapeutics AT2101) RL Lieberman et al. 2006

37. Inhibitor stabilizes protein against degradation Despite inhibition, more protein is present, accounting for increased activity Too much inhibitor leads to decreased activity Balance (correct dose) is essential.

38. Biodefense: Control of Virulence Structural Neurology: Alzheimer’s, Parkinson’s Enzyme and Pathway Evolution Structural Enzymology The Quiescent State Structural Oncology Petsko/Ringe Lab Research http://www.rose.brandeis.edu/PRLab/main.html