Interdisciplinary Life Science - PULSe Great research is a matter of choice

John Tesmer

John Tesmer Profile Picture

Walther Professor in Cancer Structural Biology
Ph.D., 1995, Purdue University


Contact Info:

jtesmer@purdue.edu
Hockmeyer Hall of Structural Biology
240 S. Martin Jischke Drive, Room 329


Training Group(s):
Biomolecular Structure and Biophysics
Molecular Signaling and Cancer Biology
Chemical Biology


Current Research Interests:

1) Molecular Basis of Heterotrimeric G Protein Function. Signal transduction conveyed from G protein-coupled receptors (GPCRs) via heterotrimeric G proteins is one of the classic paradigms of hormone action, wherein extracellular signals lead not only to transient changes in the concentrations of intracellular second messengers, but also to sustained changes such as chemotaxis, cell growth, and metastasis. Dr. Tesmer uses X-ray crystallography, cryo-electron microscopy and NMR to illuminate the mechanisms of heterotrimeric G protein signaling at atomic resolution.

2) GPCR-Linked Rho Guanine Nucleotide Exchange Factors (RhoGEFs). Sustained changes in cell behavior induced by GPCRs typically involve modulating the actin cytoskeleton and gene transcription via RhoGEFs. These enzymes play a central role in chemotaxis, tumor growth and metastasis by activating Rho GTPases. In 2004, the lab reported atomic structures of the catalytic domains of leukemia-associated RhoGEF (LARG) alone and in complex with RhoA, and in 2006, the structures of the oncogenic Gα12 and Gα13 subunits that regulate the activity of LARG. In 2007, the lab resolved the structure of the Gαq-p63RhoGEF-RhoA complex, capturing a snapshot of a novel Gαq signaling pathway implicated in the development of cardiac hypertrophy. Most recently, the Tesmer lab has been characterizing the Rac1 specific enzyme known as P-Rex1, a Gβγ-regulated RhoGEF that plays a key role in neutrophil function and in metastasis of breast and prostate cancer, and Trio, a close relative of p63RhoGEF that is responsible for tumor growth in uveal melanoma.

3) Structure and Function of G protein-coupled receptor kinases (GRKs). The ~800 GPCRs in the human genome are regulated by a family of seven vertebrate kinases that inhibit signaling by activated GPCRs, ensuring a return to homeostasis. In 2003, the Tesmer lab published the structure of the GRK2-Gβγ complex, the first of a GRK and of Gβγ subunits in complex with an effector. In 2005, the Tesmer lab reported the structure of the Gαq-GRK2-Gβγ complex, providing a snapshot of activated Gα and Gβγ subunits at the membrane as they engage a common effector target. The structure also provided the first glimpse of Gαq. The lab went on to characterize GRKs from other subfamilies: GRK6, GRK1/rhodopsin kinase, and most recently GRK5. These structures helped to identify sites that form the docking site for activated GPCRs and for anionic phospholipids. Structural characterization of a GRK-GPCR complex remains an important goal.

4) Molecular Basis of Phospholipase Activation and Reverse Cholesterol Transport. The LPLA2/LCAT family of phospholipases transfers the sn2 acyl chain from lipids such as lecithin to acceptor lipids such as ceramide or cholesterol. These closely related enzymes are important for lung surfactant catabolism and reverse cholesterol transport to the liver via HDL, respectively. They are both important targets for biotherapeutic development. The Tesmer lab has determined crystal structures for both LPLA2 and LCAT and is working towards developing small molecular activators and variants with improved activity that could be used to treat acute coronary syndrome and/or fatal genetic diseases that inhibit LCAT activity, such as familial LCAT deficiency.

5) Identification and Rational Design of Small Molecule Probes. The Tesmer lab is interested in the discovery of selective small molecule agents that can probe the above signaling cascades in more physiological contexts or that can serve as leads for drug development. Most of our published work thus far focuses on GRK inhibitors, primarily targeting GRK2, which regulates cardiac output and hypertrophy and is overexpressed during heart failure. GRK2 inhibitors have potential applications ranging from treatment of congestive heart failure to inhibition of arterial and renal plaque formation. In 2012 the lab identified the selective serotonin reuptake inhibitor paroxetine (Paxil) as a moderately selective GRK2 inhibitor, which was later shown to reverse heart malfunction in mice subjected to infarction. Using a rational approach, we have identified even more potent chemical scaffolds with distinct selectivity profiles for the various GRKs in close collaboration with medicinal chemists. New small molecule screens targeting P-Rex1 and Trio are underway to identify leads for drugs that block GPCR-linked metastasis and tumor growth, respectively.



Selected Publications:

1) Molecular Basis of Heterotrimeric G Protein Function.

Tesmer JJ, Berman DM, Gilman AG, Sprang SR. Structure of RGS4 bound to AlF4--activated G(i alpha1): stabilization of the transition state for GTP hydrolysis. Cell. 1997 Apr 18;89(2):251-61. PubMed PMID: 9108480.

Tesmer JJ, Sunahara RK, Gilman AG, Sprang SR. Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha·GTPalphaS. Science. 1997 Dec 12;278(5345):1907-16. PubMed PMID: 9417641.

Lutz S, Shankaranarayanan A, Coco C, Ridilla M, Nance MR, Vettel C, Baltus D, Evelyn CR, Neubig RR, Wieland T, Tesmer JJ. Structure of Galphaq-p63RhoGEF-RhoA complex reveals a pathway for the activation of RhoA by GPCRs. Science. 2007 Dec 21;318(5858):1923-7. PubMed PMID: 18096806.

Lyon AM, Dutta S, Boguth CA, Skiniotis G, Tesmer JJ. Full-length Galphaq-phospholipase C-β3 structure reveals interfaces of the C-terminal coiled-coil domain. Nat Struct Mol Biol. 2013 Mar;20(3):355-62. PubMed PMID: 23377541; PubMed Central PMCID: PMC3594540.

2) GPCR-Linked Rho Guanine Nucleotide Exchange Factors (RhoGEFs).

Kristelly R, Gao G, Tesmer JJ. Structural determinants of RhoA binding and nucleotide exchange in leukemia-associated Rho guanine-nucleotide exchange factor. J Biol Chem. 2004 Nov 5;279(45):47352-62. PubMed PMID: 15331592.

Kreutz B, Yau DM, Nance MR, Tanabe S, Tesmer JJ, Kozasa T. A new approach to producing functional G alpha subunits yields the activated and deactivated structures of Galpha(12/13) proteins. Biochemistry. 2006 Jan 10;45(1):167-74. PubMed PMID: 16388592; PubMed Central PMCID: PMC2688741.

Lutz S, Shankaranarayanan A, Coco C, Ridilla M, Nance MR, Vettel C, Baltus D, Evelyn CR, Neubig RR, Wieland T, Tesmer JJ. Structure of Galphaq-p63RhoGEF-RhoA complex reveals a pathway for the activation of RhoA by GPCRs. Science. 2007 Dec 21;318(5858):1923-7. PubMed PMID: 18096806.

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: PMC4860252.

3) Structure and Function of G protein-coupled receptor kinases (GRKs).

Lodowski DT, Pitcher JA, Capel WD, Lefkowitz RJ, Tesmer JJG: Keeping G proteins at bay: a complex between G protein-coupled receptor kinase 2 and Gbetagamma, Science 2003, 300: 1256-1262. PMID: 12764189.

Tesmer VM, Kawano T, Shankaranarayanan A, Kozasa T, Tesmer JJG: Snapshot of activated G proteins at the membrane: the Galphaq-GRK2-Gbetagamma complex. Science 2005, 310: 1686-1690. PMID: 16339447.

Boguth CA, Singh P, Huang C, Tesmer JJG: Molecular basis for activation of G protein-coupled receptor kinases. EMBO J, 2010, 29: 3249-59. PMCID: PMC2957210

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 JBC 2015, 290: 20649-59. PMCID: PMC4543626.

4) Molecular Basis of Phospholipase Activation and Reverse Cholesterol Transport.

Glukhova A, Hinkovska-Galcheva V, Kelly R, Abe A, Shayman JA, Tesmer JJ. Structure and function of lysosomal phospholipase A2 and lecithin:cholesterol acyltransferase. Nat Commun. 2015 Mar 2;6:6250. PMCID: PMC4397983.

Manthei KA, 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, 292:20313-20327. PMCID: PMC5724016

5) Identification and Rational Design of Small Molecule Probes.

Thal DM, Homan KT, Chen J, Wu EK, Hinkle PM, Huang ZM, Chuprun JK, Song J, Gao E, Cheung JY, Sklar LA, Koch WJ, Tesmer JJ. Paroxetine is a direct inhibitor of G protein-coupled receptor kinase 2 and increases myocardial contractility. ACS Chem Biol. 2012 Nov 16;7(11):1830-9. PubMed PMID: 22882301; PubMed Central PMCID: PMC3500392.

Schumacher SM, Gao E, Zhu W, Chen X, Chuprun JK, Feldman AM, Tesmer JJ, Koch WJ. Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction. Sci Transl Med. 2015 Mar 4;7(277):277ra31. PubMed PMID: 25739765.

Homan KT, Tesmer JJ. Molecular basis for small molecule inhibition of G protein-coupled receptor kinases. ACS Chem Biol. 2015 Jan 16;10(1):246-56. PubMed PMID: 24984143; PMCID: PMC4301174.

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: PMC5641445

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