Ernst Schonbrunn, PhD

Where You Are:
Ernst Schonbrunn, PhD

Associate Member

Office  (813) 745-4703

Education And Training
  • Fellow, Max-Planck Research Unit for Structural Molecular Biology, 1996 - Structural Molecular Biology
  • PhD, Max-Planck Research Unit for Structural Molecular Biology, 1991 - Biology/Crystallography


Research from the Schönbrunn laboratory focuses on the elucidation of the structure-activity relationship of medicinally important proteins. We use protein crystallography combined with methods in biochemistry, molecular biology and medicinal chemistry to explore proteins at the atomic level. Our aim is to identify "weak sites" in those proteins that can be targeted by new inhibitors with potential as future drugs. The spectrum of prospective drug targets under investigation in our laboratory is diverse and growing continuously:

Antibiotic targets such as MurA and EPSP synthase. Anti-cancer targets such as CDK2/cyclin A and glucometabolic enzymes. Neurodegenerative disease targets such as calpain. Male-contraceptive targets such as soluble adenylate cyclase.

We generally follow two routes towards the discovery of novel inhibitors; both these approaches become interconnected if the target protein can be crystallized. The empirical approach involves the development of an assay suitable for high-throughput screening (HTS) of hundreds of thousands of small organic compounds for inhibitory activity. Thus discovered inhibitors (hits) will be scrutinized by structure-activity relationship (SAR) and kinetic studies until the most potent inhibitors with drug-like properties (leads) have been identified. The second route is the rational design of inhibitors based on the 3D atomic structure of the target protein. First, crystallization conditions suitable for reproducible growth of X-ray quality crystals need to be established. Then, the atomic structure of the target protein will be solved by crystallographic methods, bound with ligands such as substrates, known inhibitors or newly discovered HTS hits and leads. With this information in hand, we perform several computational studies (in silico design), such as molecular docking, to identify chemical scaffolds that satisfy the criteria for high inhibitory potential. During the entire inhibitor discovery process we closely collaborate with researchers of various disciplines, from synthetic organic chemistry to cell biology, to devise strategies for the optimization of the best inhibitors with respect to drug-like properties.

Our expertise enables us to not only thoroughly characterize the molecular mode of action of inhibitors on proteins; we also perform mechanistic studies, for example to trap reaction intermediate states of enzyme-catalyzed reactions. Furthermore, we investigate the resistance of target proteins to known inhibitors. These studies complement the rational design approach, at the same time providing valuable information about the relationship of the protein's structure and function.

  • Ember SW, Zhu JY, Olesen SH, Martin MP, Becker A, Berndt N, Georg GI, Schonbrunn E. Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors. Acs Chem Biol. 2014 May;9(5):1160-1171. Pubmedid: 24568369.
  • Yang H, Lawrence HR, Kazi A, Gevariya H, Patel R, Luo Y, Rix U, Schonbrunn E, Lawrence NJ, Sebti SM. Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation. Oncotarget. 2014 May;5(10):2947-2961. Pubmedid: 24930769.
  • Olesen SH, Ingles DJ, Yang Y, Schönbrunn E. Differential antibacterial properties of the MurA inhibitors terreic acid and fosfomycin. J Basic Microbiol. 2014 Apr;54(4):322-326. Pubmedid: 23686727.
  • Martin MP, Olesen SH, Georg GI, Schonbrunn E. Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains. ACS Chem Biol. 2013 Nov;8(11):2360-2365. Pubmedid: 24007471.
  • Schonbrunn E, Betzi S, Alam R, Martin MP, Becker A, Han H, Francis R, Chakrasali R, Jakkaraj S, Kazi A, Sebti SM, Cubitt CL, Gebhard AW, Hazlehurst LA, Tash JS, Georg GI. Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases. J Med Chem. 2013 May;56(10):3768-3782. Pubmedid: 23600925. Pmcid: PMC3714109.
  • Wu S, Chen L, Becker A, Schonbrunn E, Chen J. Casein kinase 1α regulates an MDMX intramolecular interaction to stimulate p53 binding. Mol Cell Biol. 2012 Dec;32(23):4821-4832. Pubmedid: 23028042. Pmcid: PMC3497597.
  • Patel RA, Forinash KD, Pireddu R, Sun Y, Sun N, Martin MP, Schönbrunn E, Lawrence NJ, Sebti SM. RKI-1447 is a potent inhibitor of the Rho-associated ROCK kinases with anti-invasive and antitumor activities in breast cancer. Cancer Res. 2012 Oct;72(19):5025-5034. Pubmedid: 22846914. Pmcid: PMC3463757.
  • Martin MP, Alam R, Betzi S, Ingles DJ, Zhu JY, Schönbrunn E. A novel approach to the discovery of small-molecule ligands of CDK2. Chembiochem. 2012 Sep;13(14):2128-2136. Pubmedid: 22893598. Pmcid: PMC3483082.
  • Lawrence HR, Martin MP, Luo Y, Pireddu R, Yang H, Gevariya H, Ozcan S, Zhu JY, Kendig R, Rodriguez M, Elias R, Cheng JQ, Sebti SM, Schonbrunn E, Lawrence NJ. Development of o-chlorophenyl substituted pyrimidines as exceptionally potent aurora kinase inhibitors. J Med Chem. 2012 Sep;55(17):7392-7416. Pubmedid: 22803810.
  • Pireddu R, Forinash KD, Sun NN, Martin MP, Sung SS, Alexander B, Zhu JY, Guida WC, Schönbrunn E, Sebti SM, Lawrence NJ. Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2). Medchemcomm. 2012 Jun;3(6):699-709. Pubmedid: 23275831.
  • Zhu JY, Yang Y, Han H, Betzi S, Olesen SH, Marsilio F, Schönbrunn E. Functional consequence of covalent reaction of phosphoenolpyruvate with UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA). J Biol Chem. 2012 Apr;287(16):12657-12667. Pubmedid: 22378791. Pmcid: PMC3339971.
  • Lee JC, Francis S, Dutta D, Gupta V, Yang Y, Zhu JY, Tash JS, Schönbrunn E, Georg GI. Synthesis and evaluation of eight- and four-membered iminosugar analogues as inhibitors of testicular ceramide-specific glucosyltransferase, testicular β-glucosidase 2, and other glycosidases. J Org Chem. 2012 Apr;77(7):3082-3098. Pubmedid: 22432895. Pmcid: PMC3431965.
  • Martin MP, Zhu JY, Lawrence HR, Pireddu R, Luo Y, Alam R, Ozcan S, Sebti SM, Lawrence NJ, Schönbrunn E. A novel mechanism by which small molecule inhibitors induce the DFG flip in Aurora A. ACS Chem Biol. 2012 Apr;7(4):698-706. Pubmedid: 22248356.
  • Doi K, Li R, Sung SS, Wu H, Liu Y, Manieri W, Krishnegowda G, Awwad A, Dewey A, Liu X, Amin S, Cheng C, Qin Y, Schonbrunn E, Daughdrill G, Loughran TP, Sebti S, Wang HG. Discovery of marinopyrrole A (maritoclax) as a selective Mcl-1 antagonist that overcomes ABT-737 resistance by binding to and targeting Mcl-1 for proteasomal degradation. J Biol Chem. 2012 Mar;287(13):10224-10235. Pubmedid: 22311987. Pmcid: PMC3323047.
  • Li R, Martin MP, Liu Y, Wang B, Patel RA, Zhu JY, Sun N, Pireddu R, Lawrence NJ, Li J, Haura EB, Sung SS, Guida WC, Schonbrunn E, Sebti SM. Fragment-based and structure-guided discovery and optimization of rho kinase inhibitors. J Med Chem. 2012 Mar;55(5):2474-2478. Pubmedid: 22272748.
  • Pollegioni L, Schonbrunn E, Siehl D. Molecular basis of glyphosate resistance-different approaches through protein engineering. FEBS J. 2011 Aug;278(16):2753-2766. Pubmedid: 21668647. Pmcid: PMC3145815.
  • Betzi S, Alam R, Martin M, Lubbers DJ, Han H, Jakkaraj SR, Georg GI, Schönbrunn E. Discovery of a potential allosteric ligand binding site in CDK2. Acs Chem Biol. 2011 May;6(5):492-501. Pubmedid: 21291269. Pmcid: PMC3098941.
  • Mahajan K, Coppola D, Challa S, Fang B, Chen YA, Zhu W, Lopez AS, Koomen J, Engelman RW, Rivera C, Muraoka-Cook RS, Cheng JQ, Schönbrunn E, Sebti SM, Earp HS, Mahajan NP. Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS One. 2011 Jan;5(3):e9646. Pubmedid: 20333297. Pmcid: PMC2841635.
  • Berndt N, Yang H, Trinczek B, Betzi S, Zhang Z, Wu B, Lawrence NJ, Pellecchia M, Schönbrunn E, Cheng JQ, Sebti SM. The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane. Cell Death Differ. 2010 Nov;17(11):1795-1804. Pubmedid: 20489726. Pmcid: PMC2952662.
  • Han H, Yang Y, Olesen SH, Becker A, Betzi S, Schönbrunn E. The fungal product terreic acid is a covalent inhibitor of the bacterial cell wall biosynthetic enzyme UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA) . Biochemistry. 2010 May;49(19):4276-4282. Pubmedid: 20392080. Pmcid: PMC2884014.
  • Phan J, Li Z, Kasprzak A, Li B, Sebti S, Guida W, Schönbrunn E, Chen J. Structure-based design of high affinity peptides inhibiting the interaction of p53 with MDM2 and MDMX. J Biol Chem. 2010 Jan;285(3):2174-2183. Pubmedid: 19910468. Pmcid: PMC2804373.
  • Funke T, Yang Y, Han H, Healy-Fried M, Olesen S, Becker A, Schonbrunn E. Structural basis of glyphosate resistance resulting from the double mutation Thr97 -> Ile and Pro101 -> Ser in 5-enolpyruvylshikimate-3-phosphate synthase from Escherichia coli. J Biol Chem. 2009 Apr;284(15):9854-9860. Pubmedid: 19211556. Pmcid: PMC2665107.
  • Alontaga AY, Rodriguez JC, Schönbrunn E, Becker A, Funke T, Yukl ET, Hayashi T, Stobaugh J, Moënne-Loccoz P, Rivera M. Structural characterization of the hemophore HasAp from Pseudomonas aeruginosa: NMR spectroscopy reveals protein-protein interactions between Holo-HasAp and hemoglobin. Biochemistry. 2009 Jan;48(1):96-109. Pubmedid: 19072037. Pmcid: PMC2666852.
  • Wang A, Rodríguez JC, Han H, Schönbrunn E, Rivera M. X-ray crystallographic and solution state nuclear magnetic resonance spectroscopic investigations of NADP+ binding to ferredoxin NADP reductase from Pseudomonas aeruginosa. Biochemistry. 2008 Sep;47(31):8080-8093. Pubmedid: 18605699. Pmcid: PMC2792877.
  • Healy-Fried M, Funke T, Priestman M, Han H, Schonbrunn E. Structural basis of glyphosate tolerance resulting from mutations of Pro101 in Escherichia coli 5-enolpyruvylshikimate-3-phosphate synthase. J Biol Chem. 2007 Nov;282(45):32949-32955. Pubmedid: 17855366.
  • Funke T, Healy-Fried M, Han H, Alberg D, Bartlett P, Schonbrunn E. Differential inhibition of class I and class II 5-enolpyruvylshikimate-3-phosphate synthases by tetrahedral reaction intermediate analogues. Biochemistry-Us. 2007 Nov;46(46):13344-13351. Pubmedid: 17958399.
  • Wang A, Zeng Y, Han H, Weeratunga S, Morgan B, Moenne-Loccoz P, Schonbrunn E, Rivera M. Biochemical and structural characterization of Pseudomonas aeruginosa Bfd and FPR: ferredoxin NADP+ reductase and not ferredoxin is the redox partner of heme oxygenase under iron-starvation conditions. Biochemistry-Us. 2007 Oct;46(43):12198-12211. Pubmedid: 17915950.
  • Funke T, Han H, Healy-Fried ML, Fischer M, Schonbrunn E. Molecular basis for the herbicide resistance of Roundup Ready crops. Proc Natl Acad Sci U S A. 2006 Aug;103(35):13010-13015. Pubmedid: 16916934. Pmcid: PMC1559744.
  • Li Q, Hanzlik R, Weaver R, Schonbrunn E. Molecular mode of action of a covalently inhibiting peptidomimetic on the human calpain protease core. Biochemistry. 2006 Jan;45(3):701-708. Pubmedid: 16411745.
  • Priestman M, Healy M, Funke T, Becker A, Schonbrunn E. Molecular basis for the glyphosate-insensitivity of the reaction of 5-enolpyruvylshikimate 3-phosphate synthase with shikimate. FEBS Lett. 2005 Oct;579(25):5773-5780. Pubmedid: 16225867.
  • Eschenburg S, Priestman M, Abdul-Latif F, Delachaume C, Fassy F, Schonbrunn E. A novel inhibitor that suspends the induced fit mechanism of UDP-N-acetylglucosamine enolpyruvyl transferase (MurA). J Biol Chem. 2005 Apr;280(14):14070-14075. Pubmedid: 15701635.
  • Priestman MA, Healy ML, Becker A, Alberg DG, Bartlett PA, Lushington GH, Schönbrunn E. Interaction of phosphonate analogues of the tetrahedral reaction intermediate with 5-enolpyruvylshikimate-3-phosphate synthase in atomic detail. Biochemistry. 2005 Mar;44(9):3241-3248. Pubmedid: 15736934.
  • Eschenburg S, Priestman M, Schonbrunn E. Evidence that the fosfomycin target Cys115 in UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) is essential for product release. J Biol Chem. 2005 Feb;280(5):3757-3763. Pubmedid: 15531591.
  • Priestman M, Funke T, Singh I, Crupper S, Schonbrunn E. 5-Enolpyruvylshikimate-3-phosphate synthase from Staphylococcus aureus is insensitive to glyphosate. FEBS Lett. 2005 Jan;579(3):728-732. Pubmedid: 15670836.
  • Eschenburg S, Kabsch W, Healy M, Schonbrunn E. A new view of the mechanisms of UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) and 5-enolpyruvylshikimate-3-phosphate synthase (AroA) derived from X-ray structures of their tetrahedral reaction intermediate states. J Biol Chem. 2003 Dec;278(49):49215-49222. Pubmedid: 13129913.
  • Eschenburg S, Healy M, Priestman M, Lushington G, Schonbrunn E. How the mutation glycine96 to alanine confers glyphosate insensitivity to 5-enolpyruvyl shikimate-3-phosphate synthase from Escherichia coli. Planta. 2002 Nov;216(1):129-135. Pubmedid: 12430021.
  • Schonbrunn E, Eschenburg S, Shuttleworth W, Schloss J, Amrhein N, Evans J, Kabsch W. Interaction of the herbicide glyphosate with its target enzyme 5-enolpyruvylshikimate 3-phosphate synthase in atomic detail. Proc Natl Acad Sci U S A. 2001 Feb;98(4):1376-1380. Pubmedid: 11171958.
  • Eschenburg S, Schonbrunn E. Comparative X-ray analysis of the un-liganded fosfomycin-target murA. Proteins. 2000 Aug;40(2):290-298. Pubmedid: 10842342.
  • Schonbrunn E, Eschenburg S, Luger K, Kabsch W, Amrhein N. Structural basis for the interaction of the fluorescence probe 8-anilino-1-naphthalene sulfonate (ANS) with the antibiotic target MurA. Proc Natl Acad Sci U S A. 2000 Jun;97(12):6345-6349. Pubmedid: 10823915.
  • Schonbrunn E, Eschenburg S, Krekel F, Luger K, Amrhein N. Role of the loop containing residue 115 in the induced-fit mechanism of the bacterial cell wall biosynthetic enzyme MurA. Biochemistry. 2000 Mar;39(9):2164-2173. Pubmedid: 10694381.
  • Schonbrunn E, Phlippen W, Trinczek B, Sack S, Eschenburg S, Mandelkow E, Mandelkow E. Crystallization of a macromolecular ring assembly of tubulin liganded with the anti-mitotic drug podophyllotoxin. J Struct Biol. 1999 Dec;128(2):211-215. Pubmedid: 10600574.
  • Macheroux P, Schonbrunn E, Svergun D, Volkov V, Koch M, Bornemann S, Thorneley R. Evidence for a major structural change in Escherichia coli chorismate synthase induced by flavin and substrate binding. Biochem J. 1998 Oct;335 ( Pt 2):319-327. Pubmedid: 9761730 .
  • Schonbrunn E, Svergun D, Amrhein N, Koch M. Studies on the conformational changes in the bacterial cell wall biosynthetic enzyme UDP-N-acetylglucosamine enolpyruvyltransferase (MurA). Eur J Biochem. 1998 Apr;253(2):406-412. Pubmedid: 9654090 .
  • Kozielski F, Sack S, Marx A, Thormahlen M, Schonbrunn E, Biou V, Thompson A, Mandelkow E, Mandelkow E. The crystal structure of dimeric kinesin and implications for microtubule-dependent motility. Cell. 1997 Dec;91(7):985-994. Pubmedid: 9428521 .
  • Kozielski F, Schonbrunn E, Sack S, Muller J, Brady S, Mandelkow E. Crystallization and preliminary X-ray analysis of the single-headed and double-headed motor protein kinesin. J Struct Biol. 1997 Jun;119(1):28-34. Pubmedid: 9216086 .
  • Schonbrunn E, Sack S, Eschenburg S, Perrakis A, Krekel F, Amrhein N, Mandelkow E. Crystal structure of UDP-N-acetylglucosamine enolpyruvyltransferase, the target of the antibiotic fosfomycin. Structure. 1996 Sep;4(9):1065-1075. Pubmedid: 8805592 .
  • Sack S, Dauter Z, Wanke C, Amrhein N, Mandelkow E, Schonbrunn E. Crystallization and preliminary X-ray diffraction analysis of UDP-N-acetylglucosamine enolpyruvyltransferase of Enterobacter cloacae. J Struct Biol. 1996 Jul;117(1):73-76. Pubmedid: 8776890 .
  • Schweers O, Schonbrunn-Hanebeck E, Marx A, Mandelkow E. Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structure. J Biol Chem. 1994 Sep;269(39):24290-24297. Pubmedid: 7929085 .
  • Schonbrunn-Hanebeck E, Laber B, Amrhein N. Slow-binding inhibition of the Escherichia coli pyruvate dehydrogenase multienzyme complex by acetylphosphinate. Biochemistry. 1990 May;29(20):4880-4885. Pubmedid: 2194562 .
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