Professor of Biochemistry and Chemistry
Boston University, PhD
Our interests are generally in the relationship of protein three-dimensional structure to chemical function. To this end, research is focused on the modification of the catalytic properties of a number of pharmaceutically important proteins. The methods used are a combination of X-ray crystallography, design and identification of inhibitors, and site-directed mutagenesis.
The proteins being studied currently include enzymes utilizing pyridoxal phosphate or a metal ion as cofactor, a serine protease that is a pathogenesis factor from Mycobacterium tuberculosis, and a protein involved in trafficking related to Neurodegenerative Diseases.
Pyridoxal is capable of catalyzing several types of transformations. However, any one enzyme utilizing this cofactor does only one of them predominantly. The question therefore arises how the protein controls the chemical outcome of such transformations. We are studying a number of these enzymes structurally in order to begin to answer that question.
The M. tuberculosis gene product Hip1 is a serine protease that promotes pathogenesis by impairing host immune responses through proteolysis of a protein substrate GrEL2. Inhibition of this protease therefore presents a viable target as a potential therapeutic strategy against tuberculosis. We are identifying inhibitors to meet this goal. The design of such inhibitors requires detailed knowledge of the structure of the enzyme, of the enzyme complexed with inhibitors, and if possible, an understanding of the mechanisms of inhibition.
Deshpande AR, Wagenpfeil K, Pochapsky TC, Petsko GA, Ringe D. “Metal-dependent function of a mammalian acireductone dioxygenase” Biochemistry 55, 1398-407 (2016).
Wu R, Sanishvilli R, Belitsky BR, Juncosa JI, Le HV, Lehrer HJS, Farley M, Silverman RB, Petsko GA, Ringe D, Liu D, “PLP and GABAtrigger GabR-mediated transcription regulation in Bacillus subtilis via external aldimine formation” Proc. Natl. Acad. Sci. USA (2016) in press
Wang W, Nguyen LTT, Burlak C, Chegini F, Guo F, Chataway T, Ju S, Fisher O, Miller DW, Datta D, Wu F, Wu C-X, Landeru A, Wells JA, Cookson MR, Boxer MB, Thomas CJ, Wei PG, Ringe D, Petsko GA, Hoang QQ. “Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein.” Proc. Natl. Acad. Sci. USA 113, 9587– 9592 (2016).
Bassil F, Fernagut P-O, Bezard E, Hoang QQ, Ringe D, Petsko GA, Meissner WG. “Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy.” Proc. Natl. Acad. Sci. USA 113, 9593 – 9598 (2016).
Kim CH, Han BS, Moon J, Kim DJ, Shin J, Rajan S, Nguyen QT, Sohn M, Kim WG, Han M, Jeong I, Kim KS, Lee EH, Tu Y, Naffin-Olivos JL, Park CH, Ringe D, Yoon HS, Petsko GA, Kim KS. "Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson's disease." Proc Natl Acad Sci U S A. 2015 Jul 14;112(28):8756-61.
Barmada SJ, Ju S, Arjun A, Batarse A, Archbold HC, Peisach D, Li X, Zhang Y, Tank EM, Qiu H, Huang EJ, Ringe D, Petsko GA, Finkbeiner S. "Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1." Proc Natl Acad Sci U S A. 2015 Jun 23;112(25):7821-6.
Prediction of distal residue participation in enzyme catalysis. Brodkin HR, DeLateur NA, Somarowthu S, Mills CL, Novak WR, Beuning PJ, Ringe D, Ondrechen MJ. Protein Sci. 2015 May;24(5):762-78.