Dr. JOHN TESMER Walther Distinguished Professor in Cancer Structural Biology 765-494-1807 HOCK 329 jtesmer@purdue.edu Associated website(s): Lab Website , Publications

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PROFESSIONAL FACULTY RESEARCH

Structure, function, and chemical biological targeting of eukaryotic signaling proteins and cholesterol metabolizing enzymes

BIO

My lab studies the molecular basis of G protein-coupled receptor (GPCR)-mediated signal transduction using small-angle X-ray scattering, X-ray crystallography, and single particle cryo-electron microscopy (cryo-EM). By determining structures of signaling proteins alone and in complex with their various targets, we provide important insights into the molecular basis of signal transduction, explain how diseases result from dysfunctional regulation, and leverage this information to develop new therapeutic approaches. Since 1999, a focus area has been the structure, function, and inhibition of GPCR kinases (GRKs), a family of 7 enzymes in mammals that phosphorylate activated GPCRs and trigger their uncoupling from G proteins and their internalization. Our lab has a longstanding interest in rational drug design targeting GRKs, whose overexpression in disease states such as heart failure, cardiac hypertrophy, and cancer is linked to poor patient outcome. We also investigate the structure and function of other enzymes of central importance to health, including RhoGEFs essential for neutrophil chemotaxis as well as cancer metastasis and a family of acyltransferases that load HDL particles with cholesterol ester or process excess surfactants in alveolar macrophages. We have a strong extramural funding record and are currently supported by three NIH R01 grants.

I also have a strong commitment to scientific mentoring and service. I have worked with 16 post-doctoral fellows (including 11 women) and mentored 23 PhD/MS students (including 2 URM students and 12 women). Five of my graduate students have received American Heart Association (AHA) pre-doctoral fellowships, and one an F31 award. Seven of my post-doctoral trainees received AHA post-doctoral fellowships, one a American Cancer Society fellowship, and one an F32 post-doctoral fellowship. The majority of my alumni have remained in science-related fields, with 6 now employed as academic faculty and 4 as senior scientists in Pharma (including 5 women and 1 URM). I have also mentored more than 60 undergraduate researchers. I have served on multiple AHA and NIH study sections, on ASPET’s governing council, and on the editorial boards of Journal of Biological Chemistry and Molecular Pharmacology. I am also currently the director of an NIGMS T32 Molecular Biophysics Training Grant that provides advanced coursework, research, and professional development opportunities to 7 outstanding graduate students each year at Purdue.

Education

1990 B.A. Biochemistry & English,  Rice University
1995 Ph.D. Biological Sciences, Purdue University

Positions

1996 - 1999  Howard Hughes Postdoctoral Fellow, U of Texas Southwestern Medical Center at Dallas
1999 - 2005  Assistant Professor, Department of Chemistry, University of Texas at Austin
2005 - 2011  Associate Professor, Department of Pharmacology, University of Michigan
2005 - 2011  Research Associate Professor, Life Sciences Institute, University of Michigan
2011 - 2017  Professor, Life Sciences Institute, University of Michigan
2011 - 2017  Professor, Department of Pharmacology, University of Michigan
2017 - 2019  Adjunct Professor, Departments of Pharmacology and Biological Chemistry, U of Michigan
2017 -           Walther Professor in Cancer Structural Biology, Biological Sciences, Purdue University

Recognitions

2021               Distinguished Professor of Biological Sciences
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

Recent Publications

Manthei KA, Yang S-M, Baljinnyam B, Glukhova A, Chang L, Yuan W, Freeman LA, Shen M, Maloney DJ, Schwendeman A, Remaley AT, Jadhav A, and Tesmer JJG : Molecular basis for activation of lecithin:cholesterol acyltransferase (LCAT) by a high affinity chemical probe. Elife , 2018 7 : pii: e41604. doi: 10.7554/eLife.41604. PMCID: 6277198

Bandekar SJ, Arang N, Tang BA, Tully ES, Barton BL, Li S, Gutkind JS, and Tesmer JJG : Structure of the C-terminal guanine exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential. Sci Signal . 2019, 12 : pii: eaav2449. doi: 10.1126/scisignal.aav2449. PMCID: 6519057

Beyett TS, Fraley AE, Labudde E, Patra D, Coleman RC, Eguchi A, Glukhova A, Chen Q, Williams RM, Koch WJ, Sherman DH, and Tesmer JJG . Perturbation of the interactions of the lobes of calmodulin with G protein-coupled receptor kinase 5 using a natural product chemical probe. PNAS 2019, 116 :15895-15900. PMCID: 6689901.

Cash JN, Urata S, Li S, Ravala S, Avramova L, Gutkind JS, Tesmer JJG , Cianfrocco MA: Cryo-electron microscopy structure and analyses of the P-Rex1–Gβγ complex signaling scaffold. Sci. Adv. 2019, 5 : eaax8855. PMCID: 6795519

Manthei KA, Patra D, Wilson CJ, Fawaz MV, Piersimoni L, Shenkar J, Yuan W, Andrews PC, Engen JR, Schwendeman A, Ohi MD, Tesmer JJG . Structure of lecithin:cholesterol acyltransferase bound to high density lipoprotein particles. Commun. Biol. 2020, 3 :28. doi: 10.1038/s42003-019-0749-z. PMCID: 6962161

Ravala S, Hopkins JB, Plescia CB, Allgood SR, Kane MA, Cash JN, Stahelin RV, Tesmer JJG : The first DEP domain of the RhoGEF P-Rex1 autoinhibits activity and contributes to membrane binding. J. Biol. Chem . 2020, 295 :12635-12647. PMCID: 7476721

Rowlands RA, Chen Q, Bouley RA, Avramova LV, Tesmer JJG , White AD: Generation of highly selective, potent, and covalent G protein-coupled receptor kinase 5 inhibitors. J. Med. Chem. 2021, 64 :566-585 . PMCID: 7909074

Cato MC, Yen YC, Francis CJ, Elkins KE, Shareef A, Sterne-Marr R, Tesmer JJG : The open question of how GPCRs interact with GPCR kinases (GRKs). Biomolecules , 2021, 11 :447. PMCID: 8002388

Chen Q, Plasencia M, Li Z, Mukherjee S, Patra D, Chen C-L, Klose T., Yao X-Q, Kossiakoff AA, Chang L, Andrews PC, Tesmer JJG : Structures of rhodopsin in complex with G-protein-coupled receptor kinase 1. Nature , 2021, 595 :600-605. PMCID: in process.