Kushol Gupta, Ph.D.

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Research Assistant Professor of Biochemistry and Biophysics
Department: Biochemistry and Biophysics
Graduate Group Affiliations

Contact information
810 Stellar-Chance Building
422 Curie Blvd.
Department of Biochemistry and Biophysics
Philadelphia, PA 19104
Office: 267-259-0082
Lab: 215-573-7260
Education:
B.A. (Biochemistry and Music)
University of Pennsylvania, 1997.
Ph.D. (Pharmacology)
Perelman School of Medicine, University of Pennsylvania, 2003.
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Description of Research Expertise

The Structural Biology of Retroviral Integrases. Retroviral integrase (IN) catalyzes the incorporation of viral cDNA into the host genome. The design of effective pharmacological treatments remains of paramount importance to the treatment of HIV/AIDS, and detailed structural models of intact IN oligomers in their various states are essential to new structure-based drug design efforts. My work on the retroviral integrase (IN) has focused on the understanding of higher-order structure and oligomeric forms of the full-length integrase when bound to host factors and DNA, with the overall goal of determining the molecular details of the larger macromolecular assemblies that underlie the steps of retroviral integration and other stages of the viral life cycle.

My research has married X-ray crystallography and rigorous biophysical methods to approach these fundamental questions. These approaches have included the application of small angle X-ray and neutron scattering (SAXS/SANS), analytical ultracentrifugation, multi-angle light scattering, and molecular modeling. These studies have yielded understanding of the quaternary structure and stoichiometry of IN, IN-DNA, and IN-host factor assemblies.

Most recently these approaches have been brought to bear on an exciting new class of allosteric inhibitors (“ALLINIs”) that is able to inhibit IN via selective modulation of its oligomeric properties. Surprisingly, ALLINIs interfere not with DNA integration but with viral particle assembly late during HIV replication. In 2016, we reported a breakthrough in the structural biology of HIV Integrase: the first crystal structure of HIV-1 Integrase in complex with the ALLINI GSK 1264. To our knowledge, this is the first time full-length HIV-1 integrase has been crystallized. The structure shows GSK1264 bound to the dimer interface of the catalytic domain, and also positioned at this interface is a C-terminal domain (CTD) from an adjacent IN dimer. In the crystal lattice, IN forms an open polymer mediated by this interaction. Further studies of a panel of ALLINIs show that HIV escape mutants with reduced sensitivity commonly alter amino acids at or near the inhibitor-mediated interface, and that HIV escape mutations often encode substitutions that reduce multimerization.

Selected Publications

Eilers, G., Gupta, K., Allen, A., Zhou, J., Hwang, Y., Cory, M. B., Bushman, F. D., Van Duyne, G.: Influence of the amino-terminal sequence on the structure and function of HIV integrase. Retrovirology 17(1): 28, 2020.

Ronnebaum, T. A., Gupta, K., Christianson, D. W.: Higher-order oligomerization of a chimeric αβγ bifunctional diterpene synthase with prenyltransferase and class II cyclase activities is concentration-dependent. J Struct Biol 210(1): 107463, 2020.

O'Brien, E. S., Fuglestad, B., Lessen, H. J., Stetz, M. A., Lin, D. W., Marques, B. S., Gupta, K., Fleming, K. G., Wand, A. J.: Membrane Proteins Have Distinct Fast Internal Motion and Residual Conformational Entropy. Angew Chem Int Ed Engl 59(27): 11108-11114, 2020.

Gupta, K.: Hiding the Elephant in the Room with Experimental Neutrons. Biophys J 119(2): 234-235, 2020.

Fung, H. Y. J., McKibben, K. M., Ramirez, J., Gupta, K., Rhoades, E.: Structural Characterization of Tau in Fuzzy Tau:Tubulin Complexes. Structure 28(3): 378-384.e4, 2020.

Brian Fuglestad, Kushol Gupta, A. Joshua Wand, Kim A. Sharp: Water Loading Driven Size, Shape, and Composition of Cetyltrimethylammonium/Hexanol/Pentane Reverse Micelles Journal of Colloid and Interface Science 540: 207-217, March 2019.

Arturo, E. C., Gupta, K., Hansen, M. R., Borne, E., Jaffe, E. K.: Biophysical characterization of full-length human phenylalanine hydroxylase provides a deeper understanding of its quaternary structure equilibrium. J Biol Chem 294(26): 10131-10145, 2019.

Ashkar R, Bilheux HZ, Bordallo HN, Briber RM, Callaway DJE, Cheng X, Chu XQ, Curtis JE, Dadmun M, Fenimore PW, Fushman D, Gabel F, Gupta K, Heberle FA, Heinrich F, Hong L, Katsaras J, Kelman Z, Kharlampieva E, Kneller GR, Kovalevsky A, Krueger S, Langan P, Liberman RL, Liu Y, Losche M, Lyman E, Mao Y, Marino JP, Mattos C, Meilleur F, Moody PCE, Nickels JD, O’Neill H, Perez-Salas U, Peters J, Petridis L, Sokolov AP, Wager NJ, Weinrich M, Wymore T, Zhang Y, Smith JC.: Progress and Prospects for Neutron Scattering in Biological Sciences. Acta. Cryst. D. D74: 1129-1168, December 2018.

Li H, Sharp R, Rutherford K, Gupta K, Van Duyne GD.: Serine Integrase attP Binding and Specificity. Journal of Molecular Biology doi: 10.1016/j.jmb.2018.09.007, September 2018.

Ray-Gallet D, Ricketts MD, Sato Y, Gupta K, Boyarchuk E, Senda T, Marmorstein R, Almouzni G.: Functional activity of the H3.3 histone chaperone complex HIRA requires trimerization of the HIRA subunit. Nature Communications 9(1): 3103, August 2018.

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Last updated: 11/23/2021
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