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William David Tolbert, PhD

Academic Title:

Research Associate

Primary Appointment:

Biochemistry and Molecular Biology

Additional Title:

Research Associate, Vaccine Division, Institute of Human Virology

Phone (Primary):

410-706-7782

Education and Training

• Cornell University, B.A in Chemistry, 1989

• University of Virginia, M.S. in Biology, 1992

• University of Virginia, Ph.D. in Biology, 1997

• Technician/Postdoctoral Fellow, University of Kentucky, Department of Biochemistry, 1997-1999

• Postdoctoral Fellow, Cornell University, Department of Chemistry and Chemical Biology, 1999-2003

• Research Scientist, Van Andel Reserach Institute, Structural Sciences, 2003-2011

• Postdoctoral Fellow, University of Maryland School of Medicine, Institute of Human Virology and Department of Biochemistry and Molecular Biology, 2012-2017

• Reserach Associate, University of Maryland School of Medicine, Institute of Human Virology and Department of Biochemistry and Molecular Biology, 2017-present

Biosketch

I am a structural biologist who uses x-ray crystallography to gain insight into the function of proteins that would have been difficult to achieve by other methods. In my graduate work I contributed to the structural determination of two bacterial enzymes, 3-deoxy-D-manno-octulosonate-8-phosphate synthase from Escherichia coli, an enzyme essential for LPS formation in Gram-negative bacteria, and the partial complex of anthranilate synthase from Salmonella typhimurium, the first step in tryptophan biosynthesis, that could lead to the development of novel antibiotics.

In my postdoctoral work I determined the structures of several S-adenosylmethionine decarboxylase (AdoMetDC) complexes both to understand its enzymatic function and to aid in the design of novel anticancer and antitrypanosomal drugs. Inhibitors of AdoMetDC like the inhibitors of the other main branchpoint in polyamine biosynthesis, ornithine decarboxylase, have resulted in compounds that are undergoing testing as drugs for a number of human diseases. I was also involved in the structure determination of rat neurolysin, a 78 kDa zinc dependent protease involved in neuropeptide degradation, the structure determination of hepatocyte growth factor/scatter factor (HGF) splice variants, and the structure determination of serveral glucocorticoid receptor ligand complexes. We were able to engineer an antagonist version of an HGF splice variant (NK1) through mutagenesis based on structural information as well as determine the structure of a larger autoinhibited splice variant (NK2). Both HGF variants are potential therapeutics for the tyrosine kinase receptor Met which has been implicated in many human cancers.

My current research involves the characterization of protective antibody responses against HIV-1 in the design of better HIV vaccine candidates and in the development of HIV therapeutics. We have solved several antibody Fab/HIV-1 gp120 complex structures to help define the A32-like epitope region on gp120, a region that has been implicated in a protective role against HIV-1 acquisition and that displays strong antibody-dependent cell-mediated cytotoxicity (ADCC) in a viral entry assays. We have used this information to develop a stabilized gp120 fragment that displays this region and are in the process of testing it as an immunogen and possible vaccine candidate. Recently we have also elucidated the C11-like epitope region of gp120, another highly conserved region of HIV Env with a strong broadly reactive ADCC response in viral entry assays. Other projects in the lab include structures with potential cancer therapeutic peptides to MDM2/MDMX for use in stabilizing p53 an important player in our body’s cancer surveillance and clearance system.

Research/Clinical Keywords

Human immunodeficiency virus, antibody/antigen complexes, cancer therapeutics, structural biology, vaccine development

Highlighted Publications

Tolbert, WD, Gohain, N, Alsahafi, N, Van, V, Orlandi, C, Ding, S, Martin, L, Finzi, A, Lewis, GK, Ray, K and Pazgier, M.  "Targeting the Late Stage of HIV-1 Entry for Antibody-Dependent Cellular Cytotoxicity: Structural Basis for Env Epitopes in the C11 Region."  Structure. 2017 25: 1-13.

Gohain, N., Tolbert, WD, Orlandi, C., Richard, J., Ding, S., Chen, X., Bonsor, DA, Sundberg, EJ, Lu, W., Ray, K., Finzi, A., Lewis, GK, and Pazgier, M. “Molecular basis for epitope recognition by non-neutralizing anti-gp41 antibody F240.” Scientific Reports. 2016 9: 36685-36699.

Tolbert, WD, Gohain, N., Veillette, M., Chapleau, JP, Orlandi, C., Visciano, ML, Ebadi, M., DeVico, AL, Fouts, TR, Finzi, A., Lewis, GK, and Pazgier, M. “Paring Down HIV Env: Design and Crystal Structure of a Stabilized Inner Domain of HIV-1 gp120 Displaying a Major ADCC Target of the A32 Region.” Structure. 2016 24: 697–709.

Gohain, N., Tolbert, WD, Acharya, P., Yu, L., Liu, T., Zhao, P., Orlandi, C., Visciano, ML, Kamin-Lewis, R., Sajadi, MM, Martin, L., Robinson, JE, Kwong, PD, DeVico, AL, Ray, K., Lewis, GK, and Pazgier, M. “Co-crystal structures of antibody N60-i3 and antibody JR4 in complex with gp120 define more Cluster A epitopes involved in effective antibody-dependent effector function against HIV-1.” Journal of Virology. 2015 89: 8840-8854.

Acharya, P., Tolbert, WD, Gohain, N., Wu, X., Yu, L., Liu, T., Huang, W., Huang, C.-C., Kwon, YD, Louder, RK, Luongo, TS, McLellan, JS, Pancera, M., Yang, Y., Zhang, B., Flinko, R., Foulk, Jr., JS, Sajadi, MM, Kamin-Lewis, R., Robinson, JE, Martin, L., Kwong, PD, Guan, Y. DeVico, AL, Lewis, GK, and Pazgier, M. “Structural definition of an antibody-dependent cellular cytotoxicity response implicated in reduced risk for HIV-1 infection.” Journal of Virology. 2014 88: 12895-12906.

Additional Publication Citations

Richard, J., Pacheco, B., Gohain, N., Veillette, M., Ding, S., Alsahafi, N., Tolbert, WD, Prévost, J., Chapleau, J.-P., Coutu, M., Jia, M., Brassard, N., Park, J., Courter, JR, Melillo, B., Martin, L., Tremblay, C., Hahn, BH, Kaufmann, DE, Wu, X., Smith III, AB, Sodroski, J., Pazgier, M., and Finzi, A. “Co-receptor Binding Site Antibodies Enable CD4-Mimetics to Expose Conserved Anti-cluster A ADCC Epitopes on HIV-1 Envelope Glycoproteins.” EBioMedicine. 2016 12: 208-218.

Ding, S., Tolbert, WD, Prévost, J., Pacheco, B., Coutu, M., Debbeche, O., Xiang, S.-H., Pazgier, M., and Finzi, A. “A Highly Conserved gp120 Inner Domain Residue Modulates Env Conformation and Trimer Stability.” Journal of Virology. 2016 90: 8395-409.

Wang, C., Shen, M., Gohain, N., Tolbert, WD, Chen, F., Zhang, N., Yang, K., Wang, A., Su, Y., Cheng, T., Zhao, J., Pazgier, M., and Wang, J. “Design of a potent antibiotic peptide based on the active region of human defensing 5.” Journal of Medicinal Chemistry. 2015 7: 3083-3093.

He, Y., Yi, W., Powell, K., Zhou, XE, Tolbert, WD, Tang, X., Yang, J., Yang, H., Shi, J., Hou, L., Jiang, H., Melcher, K., and Xu, HE. “Structures and mechanism for the design of highly potent glucocorticoids.” Cell Research. 2014 24: 713-726.

Zhao, L., Tolbert, WD, Ericksen, B., Zhan, C., Wu, X., Yuan, W., Li, X., Pazgier, M., and Lu, W. “Single, double and quadruple alanine substitutions at oligomeric interfaces identify hydrophobicity as the key determinant of human neutrophil alpha defensin HNP1 function.” PLoS ONE. 2013 8: e78937.

Tolbert, WD, Daugherty-Holtrop, J., Gherardi, E., Vande Woude, G., and Xu, HE. “Structural basis for agonism and antagonism of hepatocyte growth factor.” Proceedings of the National Academy of Sciences of the United States of America. 2010 107: 13264-13269.

Suino-Powell, K., Xu, Y., Zhang, C., Tao, Y.-G., Tolbert, WD, Simons, Jr., SS, and Xu HE. “Doubling the size of the glucocorticoid receptor ligand binding pocket by deacylcortivazol.” Molecular and Cellular Biology. 2008 28: 1915-1923.

Tolbert, WD, Daugherty, J., Gao, C.-F., Xie, Q., Miranti, C., Gherardi, E., Vande Woude, G., and Xu, HE. “A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist.” Proceedings of the National Academy of Sciences of the United States of America. 2007 104: 14592–14597.

Tolbert, WD, Graham, DE, White, RH, and Ealick, SE. “Pyruvoyl-dependent Arginine Decarboxylase from Methanococcus jannaschii: Crystal Structures of the Self-cleaved and S53A Proenzyme Forms.” Structure. 2003 11: 285-294.

Tolbert, WD, Zhang, Y., Cottet, SE, Bennett, EM, Ekstrom, JL, Pegg, AE, and Ealick, SE. “Mechanism of Human S-Adenosylmethionine Decarboxylase Proenzyme Processing as Revealed by the Structure of the S68A Mutant.” Biochemistry. 2003 42: 2386-2395.

Ekstrom, JL, Tolbert, WD, Xiong, H., Pegg, AE, and Ealick, SE. “Structure of a Human S-Adenosylmethionine Decarboxylase Self-Processing Ester Intermediate and Mechanism of Putrescine Stimulation of Processing As Revealed by the H243A Mutant.” Biochemistry. 2001 40: 9495-9504.

Tolbert, WD, Ekstrom, JL, Mathews, II, Secrist, III, JA, Kapoor, P., Pegg, AE, and Ealick, SE. “The Structural Basis for Substrate Specificity and Inhibition of Human S-Adenosylmethionine Decarboxylase.” Biochemistry. 2001 40: 9484-9494.

Brown, CK, Madauss, K., Lian, W., Beck, MR, Tolbert, WD, and Rodgers, DW. “Structure of Neurolysin Reveals a Deep Channel that Limits Substrate Access.” Proceedings of the National Academy of Sciences of the United States of America. 2001 98: 3127-3132.

Wagner, T., Kretsinger, RH, Bauerle, R., and Tolbert, WD. “3-Deoxy-D-manno-octulosonate-8-phosphate Synthase from Escherichia coli. Model of Binding of Phosphoenolpyruvate and D-arabinose-5-phosphate.” Journal of Molecular Biology. 2000 301: 233-238.

Tolbert, WD, Chatterji, S., Bauerle, R., and Kretsinger R. “Crystallization and Preliminary Crystallographic Studies of the Anthranilate Synthase Partial Complex from Salmonella typhimurium.” Acta Crystallographica Section D. 1999 D55: 305-306.

Tolbert, WD, Moll, JR, Bauerle, R., and Kretsinger, RH. “Crystallization and Preliminary Crystallographic Studies of 3-deoxy-D-manno-octulosonate-8-phosphate Synthase from Escherichia coli.” Proteins: Structure, Function, and Genetics. 1996 24: 407-408.