Kushol Gupta, Ph.D.

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Research Assistant Professor of Biochemistry and Biophysics
Member, Center for AIDs Research (CFAR), University of Pennsylvania
Director, Johnson Foundation Structural Biology and Biophysics Core Facility Department of Biochemistry and Biophysics Perelman School of Medicine
Department: Biochemistry and Biophysics
Graduate Group Affiliations

Contact information
901C Stellar-Chance Building
422 Curie Blvd.
Department of Biochemistry and Biophysics
Philadelphia, PA 19104
Office: 215-898-0816
Lab: 215-573-7260
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

Gupta K, Wen Y, Ninan NS, Raimer AC, Sharp R, Spring AM, Sarachan KL, Johnson MC, Van Duyne GD, Matera AG.: Assembly of higher-order SMN oligomers is essential for metazoan viability and requires an exposed structural motif present in the YG zipper dimer. Nucleic Acids Res 49: 7644-7664, Jul 2021.

Gupta K, Allen A, Giraldo C, Eilers G, Sharp R, Hwang Y, Murali H, Cruz K, Janmey P, Bushman F, Van Duyne GD.: Allosteric HIV Integrase Inhibitors Promote Formation of Inactive Branched Polymers via Homomeric Carboxy-Terminal Domain Interactions. Structure 29: 213-225, Mar 2021.

Arturo EC, Merkel GW, Hansen MR, Lisowski S, Almeida D, Gupta K, Jaffe EK.: Manipulation of a cation-π sandwich reveals conformational flexibility in phenylalanine hydroxylase. Biochimie 2021.

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

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.

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.

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.

Gupta Kushol, Sharp Robert, Yuan Jimmy B, Li Huiguang, Van Duyne Gregory D: Coiled-coil interactions mediate serine integrase directionality. Nucleic acids research 45(12): 7339-7353, Jul 2017.

Gupta Kushol, Turkki Vesa, Sherrill-Mix Scott, Hwang Young, Eilers Grant, Taylor Louis, McDanal Charlene, Wang Ping, Temelkoff David, Nolte Robert T, Velthuisen Emile, Jeffrey Jerry, Van Duyne Gregory D, Bushman Frederic D: Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase. PLoS biology 14(12): e1002584, Dec 2016.

Arturo Emilia C, Gupta Kushol, Héroux Annie, Stith Linda, Cross Penelope J, Parker Emily J, Loll Patrick J, Jaffe Eileen K: First structure of full-length mammalian phenylalanine hydroxylase reveals the architecture of an autoinhibited tetramer. Proceedings of the National Academy of Sciences of the United States of America 113(9): 2394-9, Mar 2016.

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Last updated: 03/02/2023
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