Research & Clinical Summary

The Kelly lab uses complementary structural and biophysical methods to characterize the conformational changes viruses carry out in order to invade host cells. We focus on the transitions and the critical functional states that often are too transient or dynamic to characterize by classical structural methods. Understanding these events is essential to understanding mechanisms of cell entry, for understanding the activity of neutralizing antibodies, and also for developing novel antivirals that can target the virus prior to infection. Our core expertise is in using Hydrogen/Deuterium-Exchange Mass Spectrometry (HDX-MS), cryo-electron microscopy (cryo-EM) and small-angle X-ray scattering (SAXS) to monitor conformational change of protein complexes and viruses. An NIH K99/R00 Career Award supported my transition to studying influenza virus with techniques such as cryo-electron tomography and SAXS. Current projects apply cryo-ET, SAXS, and HDX-MS to dissect the spring-loaded membrane fusion mechanism of influenza virus hemagglutinin (HA) and HIV Env.

Publications

Combinatorial immune refocusing within the influenza hemagglutinin head elicits cross-neutralizing antibody responses. Dosey A, Ellis D, Boyoglu-Barnum S, Syeda H, Saunders M, Watson M, Kraft JC, Pham MN, Guttman M, Lee KK, Kanekiyo M, King NP. bioRxiv. 2023 May 24:2023.05.23.541996. doi: 10.1101/2023.05.23.541996. Preprint.

Structural dynamics reveal subtype-specific activation and inhibition of influenza virus hemagglutinin. Garcia NK, Kephart SM, Benhaim MA, Matsui T, Mileant A, Guttman M, Lee KK. J Biol Chem. 2023 Jun;299(6):104765. doi: 10.1016/j.jbc.2023.104765. Epub 2023 Apr 28.

Identification of broad, potent antibodies to functionally constrained regions of SARS-CoV-2 spike following a breakthrough infection. Guenthoer J, Lilly M, Starr TN, Dadonaite B, Lovendahl KN, Croft JT, Stoddard CI, Chohan V, Ding S, Ruiz F, Kopp MS, Finzi A, Bloom JD, Chu HY, Lee KK, Overbaugh J. bioRxiv. 2022 Dec 16:2022.12.15.520606. doi: 10.1101/2022.12.15.520606. Preprint.

hACE2-Induced Allosteric Activation in SARS-CoV versus SARS-CoV-2 Spike Assemblies Revealed by Structural Dynamics. Chen C, Zhu R, Hodge EA, Díaz-Salinas MA, Nguyen A, Munro JB, Lee KK. ACS Infect Dis. 2023 Jun 9;9(6):1180-1189. doi: 10.1021/acsinfecdis.3c00010. Epub 2023 May 11.

Vaccination with a structure-based stabilized version of malarial antigen Pfs48/45 elicits ultra-potent transmission-blocking antibody responses. McLeod B, Mabrouk MT, Miura K, Ravichandran R, Kephart S, Hailemariam S, Pham TP, Semesi A, Kucharska I, Kundu P, Huang WC, Johnson M, Blackstone A, Pettie D, Murphy M, Kraft JC, Leaf EM, Jiao Y, van de Vegte-Bolmer M, van Gemert GJ, Ramjith J, King CR, MacGill RS, Wu Y, Lee KK, Jore MM, King NP, Lovell JF, Julien JP. Immunity. 2022 Sep 13;55(9):1680-1692.e8. doi: 10.1016/j.immuni.2022.07.015. Epub 2022 Aug 16.

Visualization of conformational changes and membrane remodeling leading to genome delivery by viral class-II fusion machinery. Mangala Prasad V, Blijleven JS, Smit JM, Lee KK. Nat Commun. 2022 Aug 15;13(1):4772. doi: 10.1038/s41467-022-32431-9.

Structural dynamics reveal isolate-specific differences at neutralization epitopes on HIV Env.  Hodge EA, Naika GS, Kephart SM, Nguyen A, Zhu R, Benhaim MA, Guo W, Moore JP, Hu SL, Sanders RW, Lee KK. iScience. 2022 May 23;25(6):104449. doi: 10.1016/j.isci.2022.104449. eCollection 2022 Jun 17.

Structure-based design of stabilized recombinant influenza neuraminidase tetramers.  Ellis D, Lederhofer J, Acton OJ, Tsybovsky Y, Kephart S, Yap C, Gillespie RA, Creanga A, Olshefsky A, Stephens T, Pettie D, Murphy M, Sydeman C, Ahlrichs M, Chan S, Borst AJ, Park YJ, Lee KK, Graham BS, Veesler D, King NP, Kanekiyo M. Nat Commun. 2022 Apr 5;13(1):1825. doi: 10.1038/s41467-022-29416-z.