James R. Horn

Recipient of Northern Illinois University's Excellence in Undergraduate Teaching Award

Macromolecular Mechanisms and Interactions

A major constituent of biological regulation and activity involves macromolecule interactions, such as protein–protein and protein–small molecule interactions. These finely regulated interactions form the framework for maintaining cellular homeostasis. When unregulated, the results can lead to disease states (e.g., cancer, autoimmune diseases). Thus, proteins are frequently targets of therapeutic intervention.

It is of fundamental importance to understand the biophysical nature of the forces responsible for molecular recognition. Our lab addresses such questions through studying protein energetics, dynamics and structure. We utilize both experimental and computational/theoretical approaches toward this end. The long‐term goals of this research will aid in structure‐based drug design and the development of novel protein engineering strategies.

To help investigate structure/energetic relationships, we use a variety of protein–protein model systems, such as the camelid antibody/antigen complex shown in Figure 1. Biophysical studies using techniques such as isothermal titration calorimetry, surface plasmon resonance (SPR) and X‐ray crystallography combine to provide powerful insight into molecular recognition. In addition, we utilize protein engineering techniques such as phage display (molecular biology‐based combinatorial chemistry) to probe and explore protein–protein interactions.

Computational and theoretical techniques are also used to explore the nature of protein–protein and protein–small molecule interactions. For instance, molecular dynamic simulations are used to model features of protein dynamics that are often difficult to elucidate through experimental approaches. To model protein–small molecule interactions, molecular docking (virtual inhibitor discovery, Figure 2) is used to test and explore structural/energetic relationships. This technique also provides opportunities to discover novel inhibitors.

Figure 1Figure 1. A camelid antibody/antigen complex.

Figure 2Figure 2. Theoretical model of small‐molecule docking.

Representative Publications

Engineered synthetic antibodies as probes to quantify the energetic contributions of ligand binding to conformational changes in proteins. Somnath Mukherjee, Dionne H Griffin, James R Horn, Shahir S Rizk, Malgorzata Nocula–Lugowska, Magnus Malmqvist, Sangwoo S Kim, and Anthony A Kossiakoff (2018) Journal of Biological Chemistry, in press

Rickettsia prowazekii methionine aminopeptidase as a promising target for the development of antibacterial agents. Travis R. Helgren, Congling Chen, Phumvadee Wangtrakuldee, Thomas E. Edwards, Bart L. Staker, Jan Abendroth, Banumathi Sankaran, Nicole A. Housley, Peter J. Myler, Jonathon P. Audia, James R. Horn, and Timothy J. Hagen (2017) Bioorganic & Medicinal Chemistry, 25, p.813–824.

Site‐directed immobilization of a genetically engineered anti‐methotrexate antibody via an enzymatically introduced biotin label significantly increases the binding capacity of immunoaffinity columns
Kaitlynn R. Davenport, Christopher A. Smith, Heike Hofstetter, James R. Horn, Oliver Hofstetter (2016) Journal of Chromatography B, 1021: 114–121

Fanning, S.W., Walter, R., Horn, J.R. (2014) Structural Basis of an Engineered Dual‐Specific Antibody: Conformational Diversity Leads to a Hypervariable Loop Metal Binding Site. Protein Engineering Design and Selection 27 (10): 391–397.

Zhang, Z., Jakkaraju, S., Blain, J., Gogol, K., Zhao, L., Hartley, R.C., Karlsson, C.A., Staker, B.L., Stewart, L.J., Myler, P.J., Clare, M., Begley, D.W., Horn, J.R., Hagen, T.J. (2013) Cytidine derivatives as IspF inhibitors of Burkolderia pseudomallei. Bioorganic and Medicinal Chemistry Letters, 23(24), pp. 6860–6863.

cover2A combinatorial histidine scanning library approach to engineer highly pH‐dependent protein switches. Murtaugh, M.L.; Fanning, S.W.; Sharma, T.M.; Terry, A.M.; Horn J.R. (2011) Protein Science, 20 (9):1619–1631 (Featured Cover Art).

coverAn anti‐hapten camelid antibody reveals a cryptic binding site with significant energetic contributions from a nonhypervariable loop. Fanning, S.W.; Horn, J.R. (2011) Protein Science, 20 (7): 1196–1207 (Featured Cover Art).

A Combinatorial Approach to Engineer a Dual‐Specific Metal Switch Antibody. Fanning, S.W.; Murtaugh, M.; Horn, J.R. (2011) Biochemistry, 50 (23): 5093–5095.

James R. Horn

Interim Director of Graduate Studies
La Tourette Hall 432

Educational Background

Postdoctoral Fellow, University of Chicago, 2003–2006

Postdoctoral Fellow, Northwestern University Medical School, 2002–2003

Ph.D., University of Iowa, 2002

B.A., Knox College, 1996

Curriculum Vitae

Research Interests

Protein–protein and protein–small molecule interactions; molecular recognition; protein engineering; drug design.

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