R. Michael Garavito
Research Interests
My research involves the elucidation of structure-function
relationships in membrane proteins and molecular complexes using
macromolecular crystallography and other biophysical methods. I have
focused a significant portion of my research efforts on the development of
crystallization methods for membrane proteins and the study of membrane
protein structure and function. The research on prostaglandin H synthase
(PGHS) and mammalian hexokinases (HKs) are two of the membrane protein
projects in the laboratory. My group is also pursuing research into the
structure and function of several enzymes involved in the biosynthesis of
glycolipids and glycosteroids.
Prostaglandin endoperoxide H synthases-1 and -2 (PGHS-1 and -2) are
heme-containing, integral membrane proteins which catalyze the committed
step in the biosynthesis of prostaglandins, a large group of bioactive,
oxygenated C18-C22 compounds. PGHS-1 and -2 convert arachidonic acid to
prostaglandin H2, via the cyclooxygenase (COX) and peroxidase (POX)
reactions. Prostaglandin H2 is then converted by specific synthases into
bioactive prostaglandins and thromboxanes. The understanding the structure
and function of the PGHS isozymes has been the focus of much research
because they are the major targets of nonsteroidal anti-inflammatory drugs
(NSAIDs) which include the "over-the-counter" drugs aspirin and ibuprofen.
The PGHS isozymes have been implicated in the pathophysiology of arthritis
(inflammation and free radical damage), cardiovascular disease, cancer
(tumor production, metastasis and carcinogen activation), and various
neurological disorders like Alzheimer's and Parkinson's diseases. NSAIDs
are already used to treat symptoms of inflammatory and cardiovascular
disease. Knowledge of the structure of these enzymes is a prerequisite for
understanding how to improve our ability to control the activity of PGHS
isozymes through drug therapy.spectroscopy.MORE
Recent Publications
YF Zhang, XL Gao, RM Garavito. 2011. Biochemical characterization of human dynamin-like protein 1. Journal of Biochemistry 150: 627-633.
YF Zhang, XL Gao, Y Zheng, RM Garavito. 2011. Identification of succinic semialdehyde reductases from Geobacter: expression, purification, crystallization, preliminary functional, and crystallographic analysis. Acta Biochimica et Biophysica Sinica 43: 996-1002.
YF Zhang, XL Gao, RM Garavito. (2011) Structural analysis of the intracellular domain of (pro)renin receptor fused to maltose-binding protein. Biochemical and Biophysical Research Communications. Apr 22; 07 674-679.
Zhou R, Cusumano C, Sui D, Garavito RM, Kroos L. (2009) Intramembrane proteolytic cleavage of a membrane-tethered transcription factor by a metalloprotease depends on ATP. Proc Natl Acad Sci U S A. Sep 22;106(38):16174-9.
King JD, Poon KK, Webb NA, Anderson EM, McNally DJ, Brisson JR, Messner P, Garavito RM, Lam JS. (2009) The structural basis for catalytic function of GMD and RMD, two closely related enzymes from the GDP-D-rhamnose biosynthesis pathway. FEBS J. May;276(10):2686-700.
Gao F, Sui D, Garavito RM, Worden RM, Wang DH. (2009) Salt intake augments hypotensive effects of transient receptor potential vanilloid 4: functional significance and implication. Hypertension. Feb;53(2):228-35.
Jadhav SR, Sui D, Garavito RM, Worden RM. (2008) Fabrication of highly insulating tethered bilayer lipid membrane using yeast cell membrane fractions for measuring ion channel activity. J Colloid Interface Sci. Jun 15;322(2):465-72.
Lin, H. J., Levine, A. J., Materi, A. M., Park, J. M., Patterson, R. E., Goodmand, J. E., Chlebowski, R. T., Sansbury, L. B., Kekug, T. O., Henderson, B. E., Kolonel, L. N., Le Marchand, L., Harris, C. C., Sandler, R. S., Haile, R. W., Garavito, R. M., Lawson, J. A., and Kapoor, S. (2007) "Prostaglandin H synthase 2 (PTGS2, or Cox-2) Val511Ala variant in African Americans: pooled analyses of four case-control studies of colorectal cancer and measurements of prostaglandin synthesis and excretion in vivo." Prostaglandins, Leukotrienes and Essential Fatty Acids, in press.
Wada M, DeLong CJ, Hong YH, Rieke CJ, Song I, Sidhu RS, Yuan C, Warnock M, Schmaier AH, Yokoyama C, Smyth EM, Wilson SJ, FitzGerald GA, Garavito RM, Sui de X, Regan JW, Smith WL. (2007) Enzymes and receptors of prostaglandin pathways with arachidonic acid-derived versus eicosapentaenoic acid-derived substrates and products. J Biol Chem. 3;282(31):22254-66.
Harman CA, Turman MV, Kozak KR, Marnett LJ, Smith WL, Garavito RM. (2007) Structural basis of enantioselective inhibition of cyclooxygenase-1 by S-alpha-substituted indomethacin ethanolamides. J Biol Chem. 21;282(38):28096-105.
Qin L, Sharpe MA, Garavito RM, Ferguson-Miller S. (2007) Conserved lipid-binding sites in membrane proteins: a focus on cytochrome c oxidase. Curr Opin Struct Biol. 17(4):444-50.
Qin L, Mills DA, Hiser C, Murphree A, Garavito RM, Ferguson-Miller S, Hosler J. (2007) Crystallographic location and mutational analysis of Zn and Cd inhibitory sites and role of lipidic carboxylates in rescuing proton path mutants in cytochrome c oxidase. Biochemistry. 29;46(21):6239-48.
