My research is concerned with the three-dimensional structures
of proteins and their biochemical functions. Most of my
work is done in collaboration with Prof.
Dagmar Ringe; we share facilities, students, and a number
of projects. The tools used by our group are X-ray crystallography,
molecular biology (especially site-directed mutagenesis),
yeast genetics, organic synthesis, enzyme kinetics and molecular
dynamics calculations. These methods are being applied to
several general problems; the ones I am most involved with
include: the structural basis for efficient enzymic catalysis
of proton and hydride transfer; the role of the metal ions
in bridged bimetalloenzyme active sites; direct visualization
of proteins in action by time-resolved protein crystallography;
the evolution of new enzyme activities from old ones; and
some of these projects, we are trying to understand the
structural basis for the catalytic power of the enzymes
triose phosphate isomerase, xylose isomerase, mandelate
racemase, aminopeptidase, mutarotase and ketosteroid isomerase.
For all of them, structural information is being used to
guide site-directed mutagenesis of the active site residues
and combined quantum mechanics/molecular mechanics simulations
of the catalytic reaction.
Protein crystallography is normally a static tool and cannot
be used to follow biological reactions in real time. We
have been involved in the development of new diffraction
techniques, including Laue diffraction, that are capable
of recording entire protein crystal data sets in a millisecond.
When combined with low-temperature techniques, such methods
can be used to determine the structures of catalytic intermediates.
A new area of research in the laboratory is the use of
yeast genetics and biochemical techniques to study the quiscent
state of eukaryotic cells. We have recently shown that cells
arrest their cell cycle in G1 and then exit to the G0 state
when unfolded proteins accumulate in the cytoplasm. Accompanying
these cell cycle changes is a global shutdown in ribosomal
protein expression. This process is partly under control
of the heat shock transcription factor HSF. Another project
that uses yeast genetics and molecular biology is our attempt
to design a new metabolic pathway that will allow yeast
to grow on lactonitrile or lactamide as sole carbon sources.
The enzymes in this new pathway are being engineered from
enzymes of the mandelonitrile pathway in bacteria by a combination
of structure-directed and random mutagenesis.
Detection of ligand binding hot spots on protein surfaces via fragment-based methods: application to DJ-1 and glucocerebrosidase.
Landon MR, Lieberman RL, Hoang QQ, Ju S, Caaveiro JM, Orwig SD, Kozakov D, Brenke R, Chuang GY, Beglov D, Vajda S, Petsko GA, Ringe D. J Comput Aided Mol Des. 2009 Jun 12. [abstract]
Hydrogen Bond Coupling in the Ketosteroid Isomerase Active Site. Sigala PA, Caaveiro JM, Ringe D, Petsko GA, Herschlag D. Biochemistry. 2009 May 26. [abstract]
Effects of pH and iminosugar pharmacological chaperones on lysosomal glycosidase structure and stability. Lieberman RL, D'aquino JA, Ringe D, Petsko GA. Biochemistry. 2009 Jun 9;48(22):4816-27. [abstract]
Snapshot of a reaction intermediate: analysis of benzoylformate decarboxylase in complex with a benzoylphosphonate inhibitor. Brandt GS, Kneen MM, Chakraborty S, Baykal AT, Nemeria N, Yep A, Ruby DI, Petsko GA, Kenyon GL, McLeish MJ, Jordan F, Ringe D. Biochemistry. 2009 Apr 21;48(15):3247-57. [abstract]
A preliminary neutron diffraction study of gamma-chymotrypsin. Novak WR, Moulin AG, Blakeley MP, Schlichting I, Petsko GA, Ringe D. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2009 Mar 1;65(Pt 3):317-20. Epub 2009 Feb 26. [abstract]
Detection and time course of formation of major thiamin diphosphate-bound covalent intermediates derived from a chromophoric substrate analogue on benzoylformate decarboxylase. Chakraborty S, Nemeria NS, Balakrishnan A, Brandt GS, Kneen MM, Yep A, McLeish MJ, Kenyon GL, Petsko GA, Ringe D, Jordan F. Biochemistry. 2009 Feb 10;48(5):981-94. [abstract]
Testing geometrical discrimination within an enzyme active site: constrained hydrogen bonding in the ketosteroid isomerase oxyanion hole. Sigala PA, Kraut DA, Caaveiro JM, Pybus B, Ruben EA, Ringe D, Petsko GA, Herschlag D. J Am Chem Soc. 2008 Oct 15;130(41):13696-708. [abstract]
Mechanism of the quorum-quenching lactonase (AiiA) from Bacillus thuringiensis. 2. Substrate modeling and active site mutations.
Momb J, Wang C, Liu D, Thomas PW, Petsko GA, Guo H, Ringe D, Fast W. Biochemistry. 2008 Jul 22;47(29):7715-25. [abstract]
Mechanism of the quorum-quenching lactonase (AiiA) from Bacillus thuringiensis. 1. Product-bound structures. Liu D, Momb J, Thomas PW, Moulin A, Petsko GA, Fast W, Ringe D. Biochemistry. 2008 Jul 22;47(29):7706-14. [abstract]
Zinc coordination geometry and ligand binding affinity: the structural and kinetic analysis of the second-shell serine 228 residue and the methionine 180 residue of the aminopeptidase from Vibrio proteolyticus. Ataie NJ, Hoang QQ, Zahniser MP, Tu Y, Milne A, Petsko GA, Ringe D. Biochemistry. 2008 Jul 22;47(29):7673-83. [abstract]
Probing the active center of benzaldehyde lyase with substitutions and the pseudosubstrate analogue benzoylphosphonic acid methyl ester. Brandt GS, Nemeria N, Chakraborty S, McLeish MJ, Yep A, Kenyon GL, Petsko GA, Jordan F, Ringe D. Biochemistry. 2008 Jul 22;47(29):7734-43. [abstract]
Intrinsic motions along an enzymatic reaction trajectory. Henzler-Wildman KA, Thai V, Lei M, Ott M, Wolf-Watz M, Fenn T, Pozharski E, Wilson MA, Petsko GA, Karplus M, Hübner CG, Kern D. Nature. 2007 Dec 6;450(7171):838-44. [abstract]
Structure and specificity of a quorum-quenching lactonase (AiiB) from Agrobacterium tumefaciens. Liu D, Thomas PW, Momb J, Hoang QQ, Petsko GA, Ringe D, Fast W. Biochemistry. 2007 Oct 23;46(42):11789-99. [abstract]
Inactivation of Escherichia coli L-aspartate aminotransferase by (S)-4-amino-4,5-dihydro-2-thiophenecarboxylic acid reveals "a tale of two mechanisms". Liu D, Pozharski E, Lepore BW, Fu M, Silverman RB, Petsko GA, Ringe D. Biochemistry. 2007 Sep18;46(37):10517-27. [abstract]
X-ray crystallographic characterization of the Co(II)-substituted Tris-bound form of the aminopeptidase from Aeromonas proteolytica. Munih P, Moulin A, Stamper CC, Bennett B, Ringe D, Petsko GA, Holz RC. J Inorg Biochem. 2007 Aug;101(8):1099-107. [abstract]
of acid beta-glucosidase with pharmacological chaperone
provides insight into Gaucher disease Lieberman RL, Wustman BA, Huertas P, Powe AC Jr, Pine CW,
Khanna R, Schlossmacher MG, Ringe D, Petsko GA. (2007). Nat Chem Biol. 2007 Feb;3(2):101-107. [abstract]
crystallographic observation of an acyl-enzyme intermediate
in the elastase-catalyzed hydrolysis of a peptidyl ester
substrate: Exploiting the "glass transition" in protein
dynamics. Ding X, Rasmussen BF, Petsko GA, Ringe D. (2006) Bioorg Chem. 2006 Dec;34(6):410-23. [abstract]
Testing electrostatic complementarity
in enzyme catalysis: hydrogen bonding in the ketosteroid
isomerase oxyanion hole. Kraut DA, Sigala PA, Pybus B, Liu CW, Ringe D, Petsko GA,
Herschlag D. (2006). PLoS Biol. 2006 Apr;4(4):e99.
The high-resolution structures of the
neutral and the low pH crystals of aminopeptidase from Aeromonas
proteolytica. Desmarais W, Bienvenue DL, Bzymek KP, Petsko GA, Ringe
D, Holz RC. (2006) J Biol Inorg Chem. 2006 Jun;11(4):398-408.
basis for conformational plasticity of the Parkinson's disease-associated
ubiquitin hydrolase UCH-L1. Das C, Hoang QQ, Kreinbring CA, Luchansky SJ, Meray RK,
Ray SS, Lansbury PT, Ringe D, Petsko GA. (2006) Proc Natl Acad Sci U S A.
2006 Mar 21;103(12):4675-80. [abstract]
Multiple solvent crystal structures:
probing binding sites, plasticity and hydration. Mattos C, Bellamacina CR, Peisach E, Pereira A, Vitkup
D, Petsko GA, Ringe D. (2006) J Mol
Biol. 2006 Apr 14;357(5):1471-82. [abstract]
oxidation state of DJ-1 regulates its chaperone activity
toward alpha-synuclein. Zhou W, Zhu M, Wilson MA, Petsko GA, Fink AL. (2006) J Mol Biol. 2006 Mar 3;356(4):1036-48.
The atomic resolution
crystal structure of the YajL (ThiJ) protein from Escherichia
coli: a close prokaryotic homologue of the Parkinsonism-associated
protein DJ-1. Wilson MA, Ringe D, Petsko GA. (2005) J Mol Biol. 2005 Oct 28;353(3):678-91.
Kinetic, spectroscopic, and X-ray
crystallographic characterization of the functional E151H
aminopeptidase from Aeromonas proteolytica. Bzymek KP, Moulin A, Swierczek SI, Ringe D, Petsko GA,
Bennett B, Holz RC. (2005) Biochemistry.
2005 Sep 13;44(36):12030-40. [abstract]
Three-dimensional structure of the quorum-quenching
N-acyl homoserine lactone hydrolase from Bacillus thuringiensis. Liu D, Lepore BW, Petsko GA, Thomas PW, Stone EM, Fast
W, Ringe D. (2005) Proc Natl Acad Sci U S A. 2005 Aug 16;102(33):11882-7.
View Complete Publication List on PubMed: Gregory Petsko
Last update: May 7, 2012.