Kushol Gupta, Ph.D.
422 Curie Blvd.
Department of Biochemistry and Biophysics
Philadelphia, PA 19104
B.A. (Biochemistry and Music)
University of Pennsylvania, 1997.
Perelman School of Medicine, University of Pennsylvania, 2003.
Description of Research ExpertiseThe 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 PublicationsBrian 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.
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.
Gray KM, Kaifer KA, Baillat D, Wen Y, Bonacci TR, Ebert AD, Raimer AC, Spring AM, Have ST, Glascock JJ, Gupta K, Van Duyne GD, Emanuele MJ, Lamond AI, Wagner EJ, Lorson CL, Matera AG.: Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron. Molecular Biology of the Cell 29(2): 96-110, January 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.
Mandali Sridhar, Gupta Kushol, Dawson Anthony R, Van Duyne Gregory D, Johnson Reid C: Control of Recombination Directionality by the Listeria Phage A118 Protein Gp44 and the Coiled-Coil Motif of Its Serine Integrase. Journal of bacteriology 199(11), Jun 2017.
Gupta K: Genetics, Epigenetics and the Molecular Marks of Stress: A Primer Child abuse: Children with Disabilities. Palusci VJ, Nazer D, Greydanus DE, and Merrick J. (eds.). Nova Science 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.
Eisemann Travis, McCauley Michael, Langelier Marie-France, Gupta Kushol, Roy Swati, Van Duyne Gregory D, Pascal John M: Tankyrase-1 Ankyrin Repeats Form an Adaptable Binding Platform for Targets of ADP-Ribose Modification. Structure (London, England : 1993) 24(10): 1679-1692, Oct 2016.