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Faculty Detail    
Name CHRISTIE G BROUILLETTE
 
Campus Address CBSE 234 Zip 4400
Phone  (12-3) -234
E-mail  christie@uab.edu
Other websites
     


Faculty Appointment(s)
Appointment Type Department Division Rank
Primary  Biochemistry & Molecular Genetics  Biochemistry & Molecular Genetics Professor Emeritus
Center  Comprehensive Cancer Center  Comprehensive Cancer Center Professor Emeritus

Graduate Biomedical Sciences Affiliations
Biochemistry and Molecular Genetics Program 
Biochemistry and Structural Biology 
Biochemistry and Structural Biology 
Cellular and Molecular Biology Program 

Biographical Sketch 
Christie G. Brouillette is a chemist by training (B.S. Chemistry 1972: Ph.D. Medicinal Chemistry 1979, University of Kansas). She has been affiliated with UAB since 1979, and currently holds a research faculty appointment in the Department of Physiological Optics while serving as the Associate Director for Structural Biology in UABís Center for Biophysical Sciences and Engineering.



Research/Clinical Interest
Title
Protein Structural Cooperativity and Energetics
Description
A cooperative three-dimensional structure is essential to a proteinís biological function; it is also exploited by infectious organisms and in the design of drugs. It is the energetic consequences of structure and not the structural architecture of the protein, per se, that effects function. Two projects from my laboratory are:- Interdomain Communication in the NAD Synthetase Homodimer: NAD synthetase is an important novel enzyme for drug development. It is a ubiquitous enzyme that catalyzes the last step in the synthesis of nicotinamide adenine dinucleotide (NAD). Our x-ray crystallography results show that the substrate binding site is long and linear, with a "canyon" in the surface of the enzyme homodimer at one end, near the dimer interface, and a buried "cave" at the other end that reaches well into the interior of one of the enzyme subunits. We found the dimer is extraordinarily stable. The model for unfolding shows that the dimer is stable up until the temperature at which the protein unfolds and then unfolding and dimer dissociation occur simultaneously. In the presence of as little as 2.5% DMSO, a common solvent for the inhibitors we have designed, however, the stability of the dimer is dramatically lowered. These features have important implications for the enzyme activity, as well as for the design of enzyme inhibito- Experimental Themodynamics and Structure-Based Drug Design. Calorimetry is increasingly used in the pharmaceutical industry to accelerate the drug discovery pathway. The x-ray crystal structure of a lead receptor complex suggests a number of choices for the chemical elaboration of a lead compound. Knowledge of how the thermodynamic parameters vary with the binding of different leads can direct the choices for chemical elaboration in order to achieve greater affinity and specificity. For example, adding hydrogen bonding groups should primarily affect the DH of binding, while adding a nonpolar group to fill a hydrophobic pocket should affect primarily DS through desolvation effects.

Selected Publications 
Publication PUBMEDID
D.W. Borhani, D.P. Rogers, J.A. Engler, C.G. Brouillette. Crystal structure of truncated human apolipoprotein A-I suggests a lipid-bound conformation, Proc. Nat’l. Acad. Sci, U.S.A., 94: 12291-6, 1997.  9356442 
Protasevich, I., Yang, Z.,Wang C, Zhao, X., Atwell, S., Emtage, J.S., Wetmore, D.R., Hunt, J. F. and Brouillette, C. G., Thermal unfolding studies show the disease causing F508deletion mutation in cystic fibrosis transmembraneconductance regulator (CFTR) thermodynamically destabilizes nucleotide-binding domain 1. 2010, Protein Science. Epub 2010 Aug 04  20687133 
Moro, W.; Yang, Z.; Kane, T.; Zhou, Q.; Harville, S.; Brouillette, C.; Brouillette, W. “SAR Studies for a New Class of Antibacterial NAD Biosynthesis Inhibitors," J. Comb. Chem. 11:617-625, 2009.   19408950 
Lu S, Smith CD, Yang Z, Pruett PS, Nagy L, McCombs D, Delucas LJ, Brouillette WJ, Brouillette CG. Structure of nicotinic acid mononucleotide adenylyltransferase from Bacillus anthracis. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2008 Oct 1;64(Pt 10):893-8. Epub 2008 Sep 30.  18931430 
Protasevich II, Brouillette CG, Snow ME, Dunham S, Rubin JR, Gogliotti R, Siegel K. Role of inhibitor aliphatic chain in the thermodynamics of inhibitor binding to Escherichia coli enoyl-ACP reductase and the Phe203Leu mutant: a proposed mechanism for drug resistance. Biochemistry. 2004 Oct 26;43(42):13380-9.  15491144 
Yang ZW, Tendian SW, Carson WM, Brouillette WJ, Delucas LJ, Brouillette CG. Dimethyl sulfoxide at 2.5% (v/v) alters the structural cooperativity and unfolding mechanism of dimeric bacterial NAD+ synthetase. Protein Sci. 2004 Mar;13(3):830-41.   14978314 
J. Symersky, Y. Devedjiev, K. Moore, C.G. Brouillette, L.J. DeLucas, NH3-dependent NAD+ synthetase from Bacillus subtilis at 1Å resolution, Acta Cryst D58:1138-1146, 2002  12077433 
Y. Devedjiev, J. Symersky, R. Singh, M.J. Jedrzejas, C.G. Brouillette, W.J. Brouillette, D.D. Muccio, L.J. DeLucas. Stabilization of active site loops in NH3-dependent NAD+ synthetase from Bacillus subtilis, Acta Cryst D57:806-12, 2001.  11375500 
M.H. Parker, D.F. Ortwine, E.A. Lunney, P.M. O’Brien, C.A. Banotai, W.T. Mueller, C.G. Brouillette. Stereoselective binding of an enantiomeric pair of stromelysin-1 inhibitors caused by conformational entropy factors, Bioorg. Med. Chem. Lett. 10:2427, 2000.  11078193 
M.H. Parker, E.A. Lunney, D.F. Ortwine, A.G. Pavlovsky, C. Humblet, C.G. Brouillette. Analysis of the binding of hydroxamic acid and carboxylic acid inhibitors to the stromelysin-1(matrix metalloprote-inase-3) catalytic domain by isothermal titration calorimetry, Biochemistry 38:13592-601, 1999.  10521266 

Keywords
calorimetry, protein folding, thermodynamics, drug discovery