John Tesmer

G protein-coupled receptors (GPCRs) are responsible for the sensation of sight and smell, regulation of blood pressure and heart rate, and control of cell growth and migration. Signals impinging upon the exterior of the cell induce a conformational change in these GPCRs, instigating intracellular cascades that lead to profound physiological change. Dysfunctional signaling can lead to heart failure, hypertension, and tumor growth and metastasis. We study the molecular basis of GPCR-mediated signal transduction, principally via the technique of X-ray crystallography. By determining atomic structures of signaling proteins alone and in complex with their various targets, we can provide novel insights into the molecular basis of signal transduction and disease. The lab is also interested in rational drug design and the development of biotherapeutic enzymes. We currently have a robust drug development program aimed at a family of GPCR kinases (GRKs) wherein we are seeking to identify potent and selective inhibitors of GRKs involved in cardiovascular disease. We also are investigating GPCR regulated RhoGEFs that play significant roles in uveal melanoma and breast cancer. Another area of interest is a small family of human phospholipases that includes LPLA2, a lysosomal enzyme important for the function of alveolar macrophages, and LCAT, a key enzyme in reverse cholesterol transport. These enzymes are important biotherapeutic and small molecule targets for the treatment of high cholesterol and lipid storage diseases, respectively.

1990 - 1993     N.S.F. Predoctoral Fellowship
1994 - 1995     Purdue Research Foundation Grant
1995                H. E. Umbarger Outstanding Graduate Student Award
2000                American Heart Association Texas Affiliate Lyndon Baines Johnson Research Award
2002                Cottrell Scholar Award (Research Corporation)
2004                U. of Texas at Austin College of Natural Sciences Teaching Excellence Award
2008                Basic Science Research Award (U. Michigan Medical School)
2009                John J. Abel Award (American Society for Pharmacology and Experimental Therapeutics)
2010                American Society for Biochemistry and Molecular Biology Young Investigator Award
2013                American Association for the Advancement of Science Fellow

Glukhova A, Hinkovska-Galcheva V, Kelly R, Abe A, Shayman JA, Tesmer JJG: Structure and function of lysosomal phospholipase A2 and lecithin:cholesterol acyltransferase. Nat. Commun. 2015, 6: 6250. doi: 10.1038/ncomms7250. PMCID: 4397983

Homan KT, Waldschmidt H, Glukhova A, Cannavo A, Song J, Cheung JY, Koch WJ, Larsen SD, Tesmer JJG: Crystal structure of G protein-coupled receptor kinase 5 in complex with a rationally designed inhibitor J. Biol. Chem. 2015, 290: 20649-59. PMCID: 4543626 (Selected as “Paper of the Week”)

Taylor VG, Bommarito PA, Tesmer JJG: Structure of the regulator of G protein signaling 8 (RGS8)–Galphaq complex: molecular basis for Galpha selectivity. J. Biol. Chem. 2016, 291: 5138-45. PMCID: 4777848

Cash JN, Davis EM, Tesmer JJG: Structural and biochemical characterization of the catalytic core of the metastatic factor P-Rex1 and its regulation by PtdIns(3,4,5)P3. Structure 2016, 24: 730-40. PMCID: 4860252

Waldschmidt HV, Homan KT, Cruz-Rodríguez O, Cato MC, Waninger-Saroni J, Kirchoff P, Larimore KM, Cannovo A, Song J, Cheung JY, Koch WJ, Tesmer JJG, Larsen SD: Structure-based design, synthesis and biological evaluation of highly selective and potent G protein-coupled receptor kinase 2 inhibitors. J. Med. Chem. 2016, 59: 3793-807. PMCID: 4890168

Waldschmidt HV, Homan KT, Cato MC, Cruz-Rodríguez O, Cannavo A, Wilson MW, Song J, Cheung JY, Koch WJ, Tesmer JJG, Larsen SD: Structure-based design of highly selective and potent G protein-coupled receptor kinase 2 inhibitors based on paroxetine. J. Med. Chem. 2017, 60:3052-3069. PMCID: in process.

Yao X-Q, Cato MC, Labudde E, Beyett TS, Tesmer JJG, Grant BJ: Navigating the conformational landscape of G protein-coupled receptor kinases during allosteric activation. J. Biol. Chem. 2017, 292:16032-16043. PMCID: 5625036

Bouley R, Waldschmidt HV, Cato MC, Cannavo A, Song J, Cheung JY, Yao X-Q, Koch WJ, Larsen SD, and Tesmer JJG: Structural determinants influencing the potency and selectivity of indazole-paroxetine hybrid G protein-coupled receptor kinase 2 inhibitors. Mol. Pharmacol. 2017, in press.

Hoadley-Manthei K, Ahn J, Glukhova A, Yuan W, Larkin C, Manett TD, Chang L, Shayman JA, Axley MJ, Schwendeman A, Shayman JA, Tesmer JJG: A retractable lid in lecithin:cholesterol acyltransferase provides a structural mechanism for activation by apolipoprotein A-I. J. Biol. Chem. 2017, in press.