Biochemistry and Molecular Biology
Director, Center For Biomolecular Therapeutics
Director, The Center for Biomolecular Therapeutics (CBT) Associate Director, The Institute for Bioscience and Biotechnology Research (IBBR)
Biomedical Research Facility (BRF) 108 N. Greene St., Room 439
(410) 706-6085 (NMR Center)
Education and Training
- Muhlenberg College, BS, Chemistry, 1984
- University of North Carolina-Chapel Hill, PhD, Chemistry, 1988
- Postdoctoral Fellowship, Johns Hopkins School of Medicine, 1988-1992
As director of the Center for Biomolecular Therapeutics (CBT) at the University of Maryland, Dr. Weber manages state-of-the-art scientific studies that examine mechanisms involved in disease states, and then develops drugs to treat them. Dr. Weber was co-director of a $7.9 million federal grant to acquire a superconducting 950 MHZ Nuclear Magnetic Resonance (NMR) magnet that is helping researchers better understand such molecules and develop new agents to treat cancer, AIDS, and other diseases.
The grant - among the largest of its kind ever awarded by the National Institutes of Health’s National Center for Research Resources - makes the University of Maryland the only academic institution in the US to have a 950MHZ NMR spectrometer, and one of only two sites in the country. The eight-ton magnet produces a supercharged magnetic field that enables scientists to investigate the three-dimensional structure and dynamic properties of biological molecules and how they are altered in disease states at atomic resolution. Thus, the CBT is equipped with state-of-the-art structural biology tools among the best in the country, which will soon be complimented by new instrumentation for doing near-atomic resolution cryoEM in the fall of 2017.
Dr. Weber’s laboratory is one of many in the CBT developing small-molecule inhibitors geared to treat diseases, including in cancer, diabetes, and infectious disease. Dr. Weber serves as an editorial member of more than 10 journals and has authored more than 150 research articles and book chapters involving basic science and biomedical therapeutics advances.
Calcium-signaling, tumor suppression & cancer biology, structural biology
Melville, Z., Hernandez-Ochoa, E., Pratt, S., Liu, Y., Pierce, A., Breysse, D., Wilder, P.T., Varney, K.M., Schneider, M.F., and Weber, D.J. (2017) The activation of PKA by the calcium-binding protein S100A1 is independent of cyclic AMP, Biochemistry, 56, 2328–2337.
Roth, B. M., Godoy-Ruiz, R., Varney, K. M., Rustandi, R. R., and Weber, D. J. (2016) (1)H, (13)C, and (15)N resonance assignments of an enzymatically active domain from the catalytic component (CDTa, residues 216-420) of a binary toxin from Clostridium difficile, Biomol NMR Assign 10, 213-217.
Chen, Y., Clarke, O. B., Kim, J., Stowe, S., Kim, Y. K., Assur, Z., Cavalier, M., Godoy-Ruiz, R., von Alpen, D. C., Manzini, C., Blaner, W. S., Frank, J., Quadro, L., Weber, D. J., Shapiro, L., Hendrickson, W. A., and Mancia, F. (2016) Structure of the STRA6 receptor for retinol uptake, Science 353, 887.
Cavalier, M. C., Ansari, M. I., Pierce, A. D., Wilder, P. T., McKnight, L. E., Raman, E. P., Neau, D. B., Bezawada, P., Alasady, M. J., Charpentier, T. H., Varney, K. M., Toth, E. A., MacKerell, A. D., Jr., Coop, A., and Weber, D. J. (2016) Small Molecule Inhibitors of Ca(2+)-S100B Reveal Two Protein Conformations, J Med Chem 59, 592-608.
Bresnick, A. R., Weber, D. J., and Zimmer, D. B. (2015) S100 proteins in cancer, Nat Rev Cancer 15, 96-109.
Hartman, K. G., Vitolo, M. I., Pierce, A. D., Fox, J. M., Shapiro, P., Martin, S. S., Wilder, P. T., and Weber, D. J. (2014) Complex formation between S100B protein and the p90 ribosomal S6 kinase (RSK) in malignant melanoma is calcium-dependent and inhibits extracellular signal-regulated kinase (ERK)-mediated phosphorylation of RSK, J Biol Chem 289, 12886-12895.
Liriano, M. A., Varney, K. M., Wright, N. T., Hoffman, C. L., Toth, E. A., Ishima, R., and Weber, D. J. (2012) Target binding to S100B reduces dynamic properties and increases Ca(2+)-binding affinity for wild type and EF-hand mutant proteins, J Mol Biol 423, 365-385.
House, R. P., Pozzuto, M., Patel, P., Dulyaninova, N. G., Li, Z. H., Zencheck, W. D., Vitolo, M. I., Weber, D. J., and Bresnick, A. R. Two Functional S100A4 Monomers Are Necessary for Regulating Nonmuscle Myosin-IIA and HCT116 Cell Invasion (2011) Biochemistry, 50, 6920-6932.
Yamaguchi, N., Prosser, B.L., Ghassemi, F., Xu, L., Pasek, D.A., Eu, J.P., Hernández-Ochoa, E.O., Cannon, B.R., Wilder, P.T., Lovering, R.M., Weber, D.J., Melzer, W., Schneider, M.F., and Meissner, G. Modulation of sarcoplasmic reticulum Ca2+ release in skeletal muscle expressing ryanodine receptor impaired in regulation by calmodulin and S100A1 (2011) Am. J. Physiol. Cell, 300, 998-1012. PMC Journal - In Process.
Malashkevich, V., Dulyaninova, N.G., Liriano, M.A., Varney, K.M., Knight, D., Brenowitz, M., Weber, D.J., Almo, S.C., and Bresnick, A.R. Unique mechanism of S100A4 inhibition: Trifluoperazine- induced protein oligomerization (2010) Proc. Nat. Acad. Sci., 107, 8605-8610.PMC Journal - In Process.
Lin, J., Yang, Q., Wilder, P.T., Carrier, F., and Weber, D.J. The calcium-binding protein S100B down- regulates p53 and apoptosis in malignant melanoma (2010) J. Biol. Chem., 285, 27487-27498. PMC Journal - In Process
Wilder, P.T., Charpentier, T.H., Liriano, M.A., Gianni, K., Varney, K.M., Pozharski, E., Coop, A., Toth, E.A., MacKerell, A.D. and Weber, D.J.In vitro screening and structural characterization of inhibitors of the S100B-p53 interaction (2010) Int. J. High-Throughput Screening, 1, 109-126.NIHMSID:NIHMS199963.
Smith, J., Steward, B.J., Glaysher, S., Peregrin, K., Knight, L.A., Weber, D.J., and Cree, I.A. The effects of pentamidine on melanoma ex vivo (2010) Anti-Cancer Drugs, 21, 181-185.PMCID: PMC2866106.
Zimmer, D.Z. and Weber, D.J. The calcium-dependent interaction of S100B with its protein targets (2010) Cardiovasc. Psych. and Neurol., 2010, 1-17.
Charpentier, T.H., Thompson, L.E., Liriano, M.A., Varney, K.M., Wilder, P.T., Pozharski, E., Toth, E.A., and Weber, D.J. The effect of the CapZ peptide (TRTK-12) binding to Ca2+-S100B as examined by NMR and X-ray crystallography (2010) J. Mol. Biol., 396, 1227-1243. NIHMSID:NIHMS177816. PMCID: PMC2843395.
Malashkevich, V., Dulyaninova, N.G., Liriano, M.A., Varney, K.M., Knight, D., Brenowitz, M., Weber, D.J., Almo, S.C., and Bresnick, A.R. Unique mechanism of S100A4 inhibition: Trifluoperazine-induced protein oligomerization (2010) Proc. Nat. Acad. Sci., 107, 8605-8610. PMC Journal - In Process.
Gilquin, B., Cannon, B.R., Hubstenberger, A., Moulouel, B., Falk, E., Merle, N., Assard, N., Kieffer, S., Rousseau, D., Wilder, P.T., Weber, D.J., Baudier, J. The calcium-dependent interaction between S100B and the mitochondrial 1 AAA-ATPase 2 ATAD3A and the role of this complex in the cytoplasmic processing of ATAD3A (2010), Mol. Cell Biol., 30, 2724-2736. PMC Journal - In Process.
Weiss, M.B., Vitolo, M.I., Mohseni, M., Rosen, D.M., Denmeade, S.R., Park, B.H., Weber, D.J., and Bachman, K.E. Somatic cell knockout of p53 in human mammary epithelial cells causes chromosomal instability (2010) Oncogene, 29, 4715-4724. PMC Journal - In Process.
Lin, J., Yang, Q., Wilder, P.T., Carrier, F., and Weber, D.J. The calcium-binding protein S100B down-regulates p53 and apoptosis in malignant melanoma (2010) J. Biol. Chem., 285, 27487-27498. PMC Journal - In Process.
Wilder, P.T., Charpentier, T.H., Liriano, M.A., Gianni, K., Varney, K.M., Pozharski, E., Coop, A., Toth, E.A., MacKerell, A.D. and Weber, D.J. In vitro screening and structural characterization of inhibitors of the S100B-p53 interaction (2010) Int. J. High-Throughput Screening, 1, 109-126. NIHMSID:NIHMS199963.
Zimmer, D.Z. and Weber, D.J. The calcium-dependent interaction of S100B with its protein targets (2010) Cardiovasc. Psych. and Neurol., 2010, 1-17.
Smith, J., Steward, B.J., Glaysher, S., Peregrin, K., Knight, L.A., Weber, D.J., and Cree, I.A. The effects of pentamidine on melanoma ex vivo (2010) Anti-Cancer Drugs, 21, 181-185. NIHMSID:NIHMS189914.
Wright, N.T., Cannon, B.R., Wilder, P.T., Morgan, M.T., Varney, K.M., Zimmer, D.B., and Weber, D.J. Solution structure of S100A1 bound to the CapZ peptide TRTK-12 (2009) J. Mol. Biol., 386, 1265-1277. (NIHMSID:NIHMS120897)
Charpentier, T.H., Wilder, P.T., Liriano, M.A., Varney, K.M., Zhong, S., Coop, A., Pozharski, E., MacKerell, A.D., Toth, E.A., and Weber, D.J. Small molecules bound to unique sites in the target protein binding cleft of calcium-bound S100B as characterized by nuclear magnetic resonance (NMR) and X-ray crystallography (2009) Biochemistry, 48, 6202-6212.
Vitolo, M.I., Weiss, M.B., Szmacinski, M., Tahir, K., Waldman, T., Park, B.H., Martin, S.S., Weber, D.J., and Bachman, K.E. Deletion of PTEN promotes tumorigenic signaling, resistance to anoikis, and altered response to chemotherapeutic agents in human mammary epithelial cells (2009) Cancer Res., in press.
Wright, N.T., Cannon, B.R., Zimmer, D., and Weber, D.J. S100A1: Structure, function, and therapeutic potential (2009) Curr. Chem. Biol., 3, 138-145. (NIHMSID:NIHMS121910)
Matthews, M.M., Weber, D.J., Shapiro, P.S., Coop, A., and MacKerell, Jr., A.D. Inhibition of protein-protein interactions with low molecular weight compounds (2009) Curr. Trends Med. Chem., in press.
Hernandez-Ochoa, E., Prosser, B.L., Wright, N.T., Contreras, M., Weber, D.J., and Schneider, M.F. Augmentation of Cav1 channel current and action potential duration after uptake of S100A1 in sympathetic ganglion neurons (2009) Am J of Physiol Cell Physiol. In press.
Prosser, B.L., Wright, N.T., Hernandez-Ochoa, E., Varney, K.M., Liu, Y., Olojo, R.O., Zimmer, D.B., Weber, D.J., and Schneider, M.F. S100A1 binds to the calmodulin binding site of RyR1 and modulates skeletal muscle excitation-contraction coupling (2008) J. Biol. Chem., 283, 5046-5057. (Published before April 7, 2008; no PCMIDID).
Wright, N.T., Prosser, B.L., Varney, K.M., Zimmer, D.B., Schneider, M.F., and Weber, D.J. S100A1 and calmodulin compete for the same binding site on the ryanodine receptor (2008) J. Biol. Chem.. 283, 26676-26683. (PCMID:PMC2546546)
Wright, N.T., Inman, K.G., Levine, J.A., Cannon, B.R., Varney, K.M., and Weber, D.J. Refinement and dynamic properties of rat Ca2+-S100B (2008) J. Biomol. NMR., 42, 279-286. (NIHMSID:NIHMS6221)
Charpentier, T.H., Wilder, P.T., Liriano, M., Varney, K.M., Pozharski, E., MacKerell, A.D., Coop, A., Toth, E.A., and Weber, D.J.Divalent metal ion complexes of S100B in the absence and presence of pentamidine (2008) J. Mol. Biol. 382, 56-73. (PMCID: PMC2636698)
Malashkevich, V., Varney, K.M., Garrett, G.C., Wilder, P.T., Knight, D., Charpentier, T.H., Ramagopal, U.A., Almo, S.C., Weber, D.J., and Bresnick, A.R. Structure of Ca2+-bound S100A4 and its interaction with peptides derived from nonmuscle myosin IIA (2008) Biochemistry, 47, 5111-5126. (PMCID: PMC2633413)
Rifat, D., Wright, N.T., Varney, K.M., Weber, D.J., and Black, L.W. Restriction endonuclease inhibitor IPI* of bacteriophage T4: a novel structure for a dedicated target (2008) J. Mol. Biol. 375, 720-734. (PMCID: PMC2255585)
Markowitz, J., MacKerell, A.D. and Weber, D.J. A search for inhibitors of S100B, a member of the S100 family of calcium-binding proteins (2007) Rev. Med. Chem. 7, 609-616.
Velarde, J., Varney, K.M., Inman, K.G., Farfan, M., Dudley, E., Fletcher, J., Weber, D.J., and Nataro, J.P. Solution structure of the unique dispersin protein of enteroaggregative E. Coli (2007) Mol. Microbiol., 66, 1123-1135.
Blaustein, M.P., Charpentier, T.H., Weber, D.J. Getting a grip on calcium regulation (2007), Proc. Nat. Acad. Sci., 104, 18349-18350.
Wilder, P.T., Charpentier, T.H., and Weber, D.J. Hydrocarbon-stapled helices: A novel approach for blocking protein-protein interactions (2007) Chem. Med. Chem. 2, 1149-1151.
The major project in my laboratory involves studying the structure and function of S100B, a growth factor in the brain and skin. S100B is a dimeric Calcium-binding protein that is overproduced during gliosis in patients with Alzheimer disease, Down syndrome, and Aids related dementia. In addition, S100B and/or other members of the S100 protein family (mts1, S100ï¡, S100L, etc.) are found at high concentrations in several tumor cell lines including skin, lung, bladder, kidney, cervix, breast, head and neck, larynx, lymph, and mouth. Thus, overproduction of S100 proteins may cause problems in the regulation of cell growth in these diseases. Presumably, the function of S100B is related to its ability to bind a variety of target proteins in a Ca2+-dependent manner. One such target is the tumor suppressor protein, p53.
For this protein, we have shown that up-regulation of S100B abrogates p53 transcription activation and apoptosis in tumor cell lines and that S100B binds and inhibits both the protein kinase C-dependent phosphorylation and the oligomerization of p53. Therefore, the focus of our laboratory is to determine, at atomic resolution, the mechanism by which S100B can affect p53 transcription activation and promote uncontrolled cell growth. In this regard, we have determined the three-dimensional structure of apo-S100B and the S100B-Ca2+ complex using NMR spectroscopy, and the structure of the S100B-Ca2+-p53 peptide complex is also complete. The structural studies of S100B are imperative for the efficient design of biochemistry and the molecular biology experiments that are also done in our laboratory.
Knowledge about the structure and function of S100B are now used to design molecules that inhibit S100B from binding to p53. Patent applications are under review for several of these molecules, and perhaps one or more of these molecules will be practical as a drug for regulating uncontrolled cell growth in vivo. Similarly, structure/function studies are underway for several other members of the S100 protein family including S100A1,mts1 (S100A4), S100A2, S100A3, and others.
- Johns Hopkins University School of Medicine Young Investigator Award, 1992
- Junior Faculty Research Award, American Cancer Society, 1996
- Research Scholar Award, American Cancer Society, 2004
- Elected faculty representative for the Executive Council in the School of Medicine, 2009
- Honorary Faculty Member, University of Perugia, Perugia, Italy, 2012-present
National Institutes of Health (R01 CA177981)
MPI: Carrier, F./Weber, D.J. “Rational targeting of protein translation of cancer treatments”
National Institutes of Health (R01 EY027405)
PI: Felippo Mancia “Structural basis of receptor-mediated cellular vitamin A uptake”
US Army Medical Research Institute of Chemical Defense (Proposal no. 00226353)
PI: David J. Weber “Design of novel acetylcholinesterase reactivators”
Structural biology (NMR, X-ray, CroEM), Biochemical, Biophysical, Molecular Biology, Cell Biology, and High-Throughput Screening techniques are used in the Weber Laboratory and in the Center for Biomolecular Therapeutics.
- Director, Intercampus Biochemistry & Molecular Biology Doctoral Program, 2001-2011
- Professor & Interim Department Chair, Biochemistry & Molecular Biology, 2006-2007
- Associate Professor (tenured), 1999-2004
- Assistant Professor, 1993-1998