1. Petsko/Ringe Lab Research
Structural Enzymology
Biodefense: Control of Virulence
The Quiescent State
Structural Neurology: Alzheimer’s, Parkinson’s
Enzyme and Pathway Evolution
Structural Oncology

2. Petsko/Ringe Lab Research

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

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

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

17. DtxR: A Master Regulator of Bacterial Virulence

18. In Silico Drug Discovery

19. Sample DtxR Docking Result

20. Dagmar Ringe

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

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

23. The LactonitrilePathway
The Mandelonitrile Pathway

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

25. G0: Life in Suspension

26. Networks of Genes Involved in G0

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

28. The Anatomy of Neurodegeneration

29. Neurodegenerative Diseases
Alzheimer’s Disease (AD) - 4 million affected in U.S.
Parkinson’s Disease (PD) 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) 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. Petsko/Ringe Lab Research
Structural Enzymology
Biodefense: Control of Virulence
The Quiescent State
Structural Neurology: Alzheimer’s, Parkinson’s
Enzyme and Pathway Evolution
Structural Oncology