T. Michael Sabo, Ph.D.


B.S. in Chemistry (magna cum laude), University of Louisville, Louisville, KY; 2002
M.S. in Chemistry, University of Louisville, Louisville, KY; 2006
Ph.D. in Chemistry, University of Louisville, Louisville, KY; 2007

Curriculum Vitae

Current Positions:

Assistant Professor of Medicine, Division of Medical Oncology and Hematology, Department of Medicine, University of Louisville, Louisville, KY
Associate Faculty member, Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY
Member, Experimental Therapeutics & Diagnostics Program, James Graham Brown Cancer Center

Contact Information:

Clinical Translational Research Building, Room 217
University of Louisville
505 Hancock St.
Louisville, KY 40202, USA
Phone 502-852-3066 Fax 502-852-7979
Email: mike.sabo@louisville.edu

Research Description

Over the course of my career, the unifying theme of my research concerns elucidating the relationship between protein motion, protein structure and protein functionality.  More evidence supports moving beyond mean structural representations of proteins, i.e. X-ray crystal structures, in order to fully appreciate protein functionality.  The rich complexity of a protein’s shape-shifting (or conformational sampling) capacity has emerged as an indispensable driver of function specifically in terms of the amount and distribution of the shapes accessible to a protein during the course of its existence. Thus, the ultimate goal of the investigations within my laboratory is to provide researchers with the tools necessary to characterize these structurally silent, yet functionally important, states and motions on the atomic level with Nuclear Magnetic Resonance (NMR) Spectroscopy and exploit these “alternative” structures and functional dynamics as unique targets for future drug development efforts. Currently, there are three main projects in my laboratory:

Project 1. Human Guanylate Kinase (hGMPK): functional investigation of a new biomolecular target for lung cancer.  Being the only identified enzyme responsible for cellular GDP production, hGMPK is essential for cellular viability and proliferation of cancer cells, yet, only few studies on hGMPK exist.  Recently, we solved the first structure of a human, unliganded GMPK with NMR spectroscopy, illustrating the dynamic nature of the two nucleotide-binding regions in the absence of substrates. Also, we characterized ten cancer-associated hGMPK non-synonymous single-nucleotide variants (nsSNVs) and, quite surprisingly, observe increased catalytic activity for six nucleotide binding-site distant nsSNVs located in the CORE domain of

the kinase. Importantly, we have recent data, in collaboration with Levi Beverly, that inhibition of hGMPK in lung adenocarcinoma cell lines causes cell vulnerability without adversely affecting normal lung cells.  Our findings strongly suggest that hGMPK has the potential to be a promising biomolecular target and, with this in mind, we now have the structural data for initiating the development of novel cancer therapeutics targeting hGMPK.

Project 2. Direct Detection of Functional Sub-States in Proteins. Physiological processes, such as biomolecular recognition and enzymatic catalysis, harness protein structural dynamics for functionality.  However, the routine characterization of the biologically important and structurally silent functional states within a conformational ensemble remains elusive and is currently applicable to only the most well-behaved systems. We are attempting to define the minimal amount of NMR data that is necessary for generating high quality structural protein ensembles. We anticipate this methodology offering unprecedented possibilities for application to a wide range of biological systems in order to identify distinct and/or unique functional states. Currently, we are applying the framework to ubiquitin, the third immunoglobulin domain of protein G (GB3), and hen-egg white lysozyme.

Project 3. The structural and biophysical investigation of the metastasis promoting protein AF1q.  Dr. William Tse’s laboratory has identified AF1q as a novel co-factor that specifically binds to TCF7 in the Wnt signaling pathway. This interaction results in the activation of CD44 and multiple downstream targets of TCF7/LEF1. Furthermore, AF1q is over expressed in breast cancer (Oncotarget 24(6):20697-710, 2015), providing the impetus for us to investigate the interaction of AF1q with TCF7. Presently we are over-expressing these two proteins in E. coli in preparation for future investigations with NMR and other biophysical techniques, in an attempt to solve the first structure of AF1q and to characterize the structural dynamics important for AF1q functionality. Given that AF1q is associated with the paralleled activation of the Wnt and STAT3 signaling pathways, leading to increased motility and invasiveness in these types of cancer cells, we feel that AF1q is a promising protein drug target for many types of cancer that are dysregulated within this group of signaling pathways.

Representative Publicatoins:

  1. Sabo TM, Gapsys V, Walter KFA, Fenwick RB, Becker S, Salvatella X, de Groot BL, Lee D, Griesinger C.  Utilizing dipole-dipole cross-correlated relaxation for the measurement of angles between pairs of opposing CαHα-CαHα bonds in anti-parallel β-sheets.  Methods 2018 Apr 1;138-139:85-92.  PMID: 29656081.
  2. Khan N, Ban D, Trigo-Mourino P, Carneiro MG, Konrad M, Lee D, Sabo TM.  1H, 13C and 15N resonance assignment of human guanylate kinase.  Biomolecular NMR Assignments 2018 Apr;12(1):11-4.  PMID: 28861857.
  3. Billur R, Ban D, Sabo TM, Maurer MC.  Deciphering conformational changes associated with the maturation of thrombin anion binding exosite I.  Biochemistry 2017 Dec 5;56(48):6343-54.  PMID: 29111672.
  4. Pratihar S, Sabo TM, Ban D, Fenwick RB, Becker S, Salvatella X, Griesinger C, Lee D.  Kinetics of the antibody recognition site in the third IgG-binding domain of protein G.  Angewandte Chemie International Edition 2016 Aug 8;55(33):9567-70.  PMID: 27345359.
  5. Sabo TM, Trent JO, Lee D.  Population shuffling between ground and high energy excited states.  Protein Science 2015 Nov;24(11):1714-9.  PMID: 26316263.  PMCID: PMC4622205.
  6. Carneiro MG, Koharudin LM, Ban D, Sabo TM, Trigo-Mourino P, Mazur A, Griesinger C, Gronenborn AM, Lee D.  Sampling of glycan-bound conformers by the anti-HIV lectin Oscillatoria agardhii agglutinin in the absence of sugar.  Angewandte Chemie International Edition 2015 May;54(22):6462-5.  PMID: 25373445.  PMCID: PMC4480336.
  7. Kim DH, Lee C, Cho YJ, Lee SH, Cha EJ, Lim JE, Sabo TM, Griesinger C, Lee D, Han KH.  A pre-structured helix in the intrinsically disordered 4EBP1.  Molecular BioSystems 2015 Feb;11(2):366-9.  PMID: 25431930.
  8. Michielssens S, Peters JH, Ban D, Pratihar S, Seeliger D, Sharma M, Giller K, Sabo TM, Becker S, Lee D, Griesinger C, de Groot BL.  A designed conformational shift to control protein binding specificity.  Angewandte Chemie International Edition 2014 Sep 22;53(39):10367-71.  PMID: 25115701.  PMCID: PMC4497613.
  9. Bibow S, Carneiro MG, Sabo TM, Schwiegk C, Becker S, Riek R, Lee D.  Measuring membrane protein bond conformations in nanodiscs via residual dipolar couplings.  Protein Science 2014 Jul;23(7):851-6.  PMID: 24752984.  PMCID: PMC4088909.
  10. Sabo TM, Smith CA, Ban D, Mazur A, Lee D, Griesinger C.  ORIUM: Optimized RDC based Iterative and Unified Model-free analysis.  Journal of Biomolecular NMR 2014 Apr;58(4):287-301.  PMID: 24013952.  PMCID: PMC3982212.
  11. Ban D, Sabo TM, Griesinger C, Lee D.  Measuring dynamic and kinetic information in the previously inaccessible supra-tc window of nanoseconds to microseconds by solution NMR spectroscopy.  Molecules 2013 Sep 26;18(10):11904-37.  PMID: 24077173.  [ http://www.mdpi.com/1420-3049/18/10/11904/htm ]
  12. Ban D, Mazur A, Carneiro MG, Sabo TM, Giller K, Koharudin LMI, Becker S, Gronenborn AM, Griesinger C, Lee D.  Enhanced accuracy of kinetic information from CTCPMG experiments by transverse rotating-frame spectroscopy.  Journal of Biomolecular NMR 2013 Sep;57(1):73-82.  PMID: 23949308.
  13. Malovichko MV, Sabo TM, Maurer MC.  Ligand binding to anion binding exosites regulates conformational properties of thrombin.  Journal of Biological Chemistry 2013 Mar 22;288(12):8667-78.  PMID: 23378535.  PMCID: PMC3605685.
  14. Sabo TM, Bakhtiari D, Walter KFA, McFeeters RL, Giller K, Becker S, Griesinger C, Lee D.  Thermal coefficients of the methyl groups within ubiquitin.  Protein Science 2012 Apr;21(4):562-70.  PMID: 22334336.  PMCID: PMC3375756.
  15. Ban D, Funk M, Gulich R, Egger D, Sabo TM, Walter KFA, Fenwick RB, Giller K, Pichierri F, de Groot BL, Lange OF, Grubmüller H, Salvatella X, Wolf M, Loidl A, Kree R, Becker S, Lakomek NA, Lee D, Lunkenheimer P, Griesinger C.  Kinetics of conformational sampling in ubiquitin.  Angewandte Chemie International Edition 2011 Nov 25;50(48):11437-40.  PMID: 22113802.
  16. Sabo TM, Maurer MC.  Biophysical investigation of GpIba binding to thrombin anion binding exosite II.  Biochemistry 2009 Aug 4;48(30):7110-22.  PMID: 19591434. PMCID: PMC2842903.
  17. Cleary DB, Doiphode PG, Sabo TM, Maurer MC.  A non-reactive glutamine residue of a2-antiplasmin promotes interactions with the factor XIII active site region.  Journal of Thrombosis & Haemostasis 2009 Nov;7(11):1947-9.  PMID: 19691486.  PMCID: PMC4685669.
  18. Sabo TM, Brasher PB, Maurer MC.  Perturbations in Factor XIII resulting from activation and inhibition examined by solution based methods and detected by MALDI-TOF MS. Biochemistry 2007 Sep 4;46(38):10089-101.  PMID: 17691819.
  19. Sabo TM, Farrell DH, Maurer MC.  Conformational analysis of gammaʹ peptide (410-427) interactions with thrombin anion binding exosite II.  Biochemistry 2006 Jun 20;45(24):7434-45.  PMID: 16768439.
  20. Turner BT, Sabo TM, Wilding D, Maurer MC.  Mapping of factor XIII solvent accessibility as a function of activation state using chemical modification methods.  Biochemistry 2004 Aug 3;43(30):9755-65.  PMID: 15274630.

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