Assistant Professor
Ph.D., University Frankfurt, 2001
jens.meiler@vanderbilt.edu
Meiler Lab

Structural and Chemical Biology

Research in our laboratory seeks to fuse computational and experimental efforts to investigate proteins, the fundamental molecules of biology, and their interactions with small molecule substrates, therapeutics, or probes. We develop computational methods with three major ambitions in mind: 1) to enable protein structure elucidation of membrane proteins – the primary target of most therapeutics – and large macromolecular complexes such as viruses; 2) design proteins with novel structure and/or function to explore novel approaches to protein therapeutics and deepen our understanding of protein folding pathways, and 3) understand the relation between chemical structure and biological activity quantitatively in order to design more efficient and more specific drugs. Crucial for our success is the experimental validation of our computational approaches which we pursue in our laboratory or in collaboration with other scientists. For a complete list of research projects please visit www.meilerlab.org.
Current research projects include:

1) Protein Structure Elucidation of EMRE. EmrE is a 12 kDa small multidrug resistant transporter (SMR) protein. It contributes to multidrug resistance in cancer and bacterial cells by removing compounds toxic to the cell such as the therapeutics. EmrE has been shown to contain four transmembrane α-helices and form a homodimer. While X-Ray crystallography and NMR spectroscopy frequently yield datasets for membrane proteins that are of lesser quality and/or sparse compared to soluble proteins, extensive Electron Paramagnetic Resonance (EPR) and cryo-Electron Microscopy (cryo-EM) datasets are available for EmrE. We develop computer algorithms tailored for determining the structure from these low resolution/sparse experimental data with the ultimate goal of solving the structure of EmrE and other membrane proteins. By determining the structure of EmrE, novel chemotherapeutic agents could be developed, including those to combat multidrug resistance.







2) Design of Protein Antibiotics. Gram positive bacterial infections are a significant global cause of human mortality. More than 125,000 people contract multidrug-resistant gram positive infections annually in the U.S. alone, resulting in more than 40,000 deaths per year. Vancomycin is the last-line antibiotic for gram-positive infections. It kills bacteria by binding the -D-ala-D-ala C-terminus of a key bacterial cell wall glycopeptide component, thereby inhibiting proper cell wall biosynthesis. The most common mechanism of acquired resistance is through the substitution of a -D-lac in place of the -D-ala at the C-terminus of the bacterial glycopeptide. The goal of this project is to explore a rational design approach to develop novel antimicrobial protein therapeutics capable of binding both the multidrug-resistant -D-ala-D-ala and vancomycin-resistant -D-ala-D-lac target peptides.







3) Novel Schizophrenia Therapeutics by Virtual High-Throughput Screening. Selective potentiators of the metabotropic glutamate receptor subtype mGluR5 have exciting potential for development of novel treatment strategies for schizophrenia. A high-throughput screen (HTS) for mGluR5 potentiators at Vanderbilt’s molecular libraries screening center network facility revealed a large and diverse set of about 1,400 substances. We utilize the power of recent machine learning techniques such as Artificial Neural Networks (ANNs) and Support Vector Machines (SVMs) to model the complex relationship between chemical structure and biological activity of mGluR5 potentiators. These models will be used to virtually screen millions of compounds for activity and guide chemical synthesis of novel compounds.

Selected Publications

Kaufmann KW, Dawson ES, Henry LK, Field JR, Blakely RD, Meiler J. Structural determinants of species-selective substrate recognition in human and Drosaphila serotonin transporters revealed through computational docking studies. Proteins-Structure Function and Bioinformatics. 2009, 74 (3): 630-642.

Fallen K, Banerjee S, Sheehan J, Addison D, Lewis LM, Meiler J, Denton JS. The Kir channel immunoglobulin domain is essential for Kir1.1 (ROMK) thermodynamic stability, trafficking and gating. Channels. 2009, 3 (1): 57-68.

Lindert S, Stewart PL, Meiler J. Hybrid approaches: applying computational methods in cryo-electron microscopy. Current Opinion in Structural Biology. 2009, 19 (2): 218-225.

Koehler J, Woetzel N, Staritzbichler R, Sanders CR, Meiler J. A unified hydrophobicity scale for multispan membrane proteins. Proteins-Structure Function and Bioinformatics. 2009, 76 (1): 13-29.

Stepanovic SZ, Potet F, Petersen CI, Smith JA, Meiler J, Balser JR, Kupershmidt S. The evolutionarily conserved residue A653 plays a key role in HERG channel closing. Journal of Physiology-London. 2009, 587 (11): 2555-2566.

Lange OF, Lakomek NA, Fares C, Schroder GF, Walter KFA, Becker S, Meiler J, Grubmuller H, Griesinger C, de Groot BL. Recognition dynamics up to microseconds revealed from an RDC-derived ubiquitin ensemble in solution. Science. 2008, 320 (5882): 1471-1475.

Hanson SM, Dawson ES, Francis DJ, Van Eps N, Klug CS, Hubbell WL, Meiler J, Gurevich VV. A model for the solution structure of the rod arrestin tetramer. Structure. 2008, 16 (6): 924-934.

Lakomek NA, Walter KFA, Fares C, Lange OF, de Groot BL, Grubmuller H, Bruschweiler R, Munk A, Becker S, Meiler J, Griesinger C. Self-consistent residual dipolar coupling based model-free analysis for the robust determination of nanosecond to microsecond protein dynamics. Journal of Biomolecular NMR. 2008, 41 (3): 139-155.

Kang CB, Tian CL, Sonnichsen FD, Smith JA, Meiler J, George AL, Vanoye CG, Kim HJ, Sanders CR. Structure of KCNE1 and implications for how it modulates the KCNQ1 potassium channel. Biochemistry. 2008, 47 (31): 7999-8006.

Alexander N, Al-Mestarihi A, Bortolus M, McHaourab H, Meiler J. De Novo High-Resolution Protein Structure Determination from Sparse Spin-Labeling EPR Data. Structure. 2008, 16: 181-95.

Field JR, Kaufmann K W, Meiler J, Blakely RD. Model-guided exploration of the serotonin transporter: Evaluation of residues engaged in substrate binding and selectivity. Journal of Neurochemistry. 2007, 102: 45-45.

McKinney BA, Kallewaard NL, Crowe JE, Meiler J. Using the natural evolution of a rotavirus-specific human monoclonal antibody to predict the complex topography of a viral antigenic site. Immunome Research. 2007, 3: 8.

Henry LK, Meiler J, Blakely RD. Bound to be different: Neurotransmitter transporters meet their bacterial cousins. Molecular Interventions. 2007, 7 (6): 306-309.

Smith JA, Vanoye CG, George AL, Meiler J, Sanders CR. Structural models for the KCNQ1 voltage-gated potassium channel. Biochemistry. 2007, 46 (49): 14141-14152.

Reese M, Sanchez-Pedregal VM, Kubicek K, Meiler J, Blommers MJJ, Griesinger C, Carlomagno T. Structural basis of the activity of the microtubule-stabilizing agent epothilone A studied by NMR spectroscopy in solution. Angewandte Chemie-International Edition. 2007, 46 (11): 1864-1868.

Sanchez-Pedregal VM, Kubicek K, Meiler J, Lyothier I, Paterson I, Carlomagno T. The tubulin-bound conformation of discodermolide derived by NMR studies in solution supports a common pharmacophore model for epothilone and discodermolide. Angewandte Chemie-International Edition. 2006, 45: 7388-94.

Zanghellini A, Jiang L, Wollacott AM, Cheng G, Meiler J, Althoff EA, Rothlisberger D, Baker D. New algorithms and an in silico benchmark for computational enzyme design. Protein Science. 2006, 15: 2785-94.

Meiler J, Baker D. ROSETTALIGAND: Protein-small molecule docking with full side-chain flexibility. Proteins-Structure Function And Bioinformatics. 2006, 65 (3): 538-548.

Lakomek NA, Carlomagno T, Becker S, Griesinger C, Meiler J. A thorough dynamic interpretation of residual dipolar couplings in ubiquitin. Journal of Biomolecular NMR. 2006, 34 (2): 101-115.

Bradley P, Malmstrom L, Qian B, Schonbrun J, Chivian D, Kim DE, Meiler J, Misura KM, Baker D. Free modeling with Rosetta in CASP6. Proteins. 2005, 61 Suppl 7: 128-34.

Lakomek NA, Fares C, Becker S, Carlomagno T, Meiler J, Griesinger C. Side-chain orientation and hydrogen-bonding imprint supra-tau(c) motion on the protein backbone of ubiquitin. Angewandte Chemie-International Edition. 2005, 44 (47): 7776-7778.

Grana O, Baker D, MacCallum RM, Meiler J, Punta M, Rost B, Tress ML, Valencia A. CASP6 assessment of contact prediction. Proteins-Structure Function and Bioinformatics. 2005, 61: 214-224 Suppl. 7.

Meiler J, Baker D. The fumarate sensor DcuS: progress in rapid protein fold elucidation by combining protein structure prediction methods with NMR spectroscopy. Journal of Magnetic Resonance. 2005, 173 (2): 310-316.

Sanchez-Pedregal VM, Reese M, Meiler J, Blommers MJJ, Griesinger C, Carlomagno T. The INPHARMA method: Protein-mediated interligand NOEs for pharmacophore mapping. Angewandte Chemie-International Edition. 2005, 44 (27): 4172-4175.

Meiler J, Kock M. Novel methods of automated structure elucidation based on C-13 NMR spectroscopy. Magnetic Resonance in Chemistry. 2004, 42 (12): 1042-1045.

Specialties

• Computational Structural Biochemistry
• Chemical Biology

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