School of Pharmacy

Kelly Lee

Professor, Medicinal Chemistry

Department of Medicinal Chemistry, Lee Lab, Medicinal Chemistry Faculty, School Faculty

Telephone: (206) 616-3972

Email: kklee@uw.edu

Website: Lee Lab

Education

  • AB (Honors), Harvard University
  • PhD, Johns Hopkins University

Research Interests

  • HIV, Influenza A virus
  • Biophysical, structural, and biochemical techniques including X-ray scattering, cryo-electron microscopy, hydrogen/deuterium-exchange mass spectrometry, and fluorescence microscopy to understand the function of viral machinery

Taking Students: Yes

Biography

Our 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.

For example, in recent studies using cryo-ET and HDX-MS, for the first time we have been able to visualize the nature of fusion protein-mediated membrane remodeling and to determine the sequence of events in whole viruses and isolated fusion proteins that are needed to produce efficient fusion.

With the support of a Center for AIDS Research Creative and Novel Ideas in HIV Research (CNIHR) award for new investigators and with Gates Foundation support, my lab is working with Shiu-Lok Hu’s group (Pharmaceutics) to investigate the structural basis for antigenicity and immunogenicity of HIV Env glycoproteins. In addition, we have been able to characterize isolate-specific structural differences and their impact on antigenicity of Env; these effects are difficult to study by conventional approaches. Our biophysical approaches have also enabled us to analyze CD4 receptor, entry inhibitors, and neutralizing Abs in complex with the native-like HIV Env trimers. In collaboration with Julie Overbaugh’s group at the Fred Hutchinson Cancer Research Center, we are gaining insight into the nature of Env-dependent HIV transmission and the development of neutralizing antibodies in response to infection.

Dr. Lee also holds an adjunct appointment in the UW Microbiology Department and is a member of a number of cross-departmental graduate programs including the Biological Physics Structure and Design Program, the Pathobiology Graduate Program and the Molecular and Cellular Biology Program.

Recent Publications

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.

Structure-guided changes at the V2 apex of HIV-1 clade C trimer enhance elicitation of autologous neutralizing and broad V1V2-scaffold antibodies.  Sahoo A, Hodge EA, LaBranche CC, Styles TM, Shen X, Cheedarla N, Shiferaw A, Ozorowski G, Lee WH, Ward AB, Tomaras GD, Montefiori DC, Irvine DJ, Lee KK, Amara RR. Cell Rep. 2022 Mar 1;38(9):110436. doi: 10.1016/j.celrep.2022.110436.

Cryo-ET of Env on intact HIV virions reveals structural variation and positioning on the Gag lattice.  Mangala Prasad V, Leaman DP, Lovendahl KN, Croft JT, Benhaim MA, Hodge EA, Zwick MB, Lee KK. Cell. 2022 Feb 17;185(4):641-653.e17. doi: 10.1016/j.cell.2022.01.013. Epub 2022 Feb 4.

Mannose-binding lectin and complement mediate follicular localization and enhanced immunogenicity of diverse protein nanoparticle immunogens.  Read BJ, Won L, Kraft JC, Sappington I, Aung A, Wu S, Bals J, Chen C, Lee KK, Lingwood D, King NP, Irvine DJ. Cell Rep. 2022 Jan 11;38(2):110217. doi: 10.1016/j.celrep.2021.110217.

How a broadly neutralizing antibody grapples with antigenic and conformational diversity in dengue virus.  Lee KK. Cell. 2021 Dec 9;184(25):6015-6016. doi: 10.1016/j.cell.2021.11.020. Epub 2021 Dec 1.

Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization.  Aljedani SS, Liban TJ, Tran K, Phad G, Singh S, Dubrovskaya V, Pushparaj P, Martinez-Murillo P, Rodarte J, Mileant A, Mangala Prasad V, Kinzelman R, O’Dell S, Mascola JR, Lee KK, Karlsson Hedestam GB, Wyatt RT, Pancera M. PLoS Pathog. 2021 Sep 24;17(9):e1009543. doi: 10.1371/journal.ppat.1009543. eCollection 2021 Sep.

Stabilization of the SARS-CoV-2 Spike Receptor-Binding Domain Using Deep Mutational Scanning and Structure-Based Design.  Ellis D, Brunette N, Crawford KHD, Walls AC, Pham MN, Chen C, Herpoldt KL, Fiala B, Murphy M, Pettie D, Kraft JC, Malone KD, Navarro MJ, Ogohara C, Kepl E, Ravichandran R, Sydeman C, Ahlrichs M, Johnson M, Blackstone A, Carter L, Starr TN, Greaney AJ, Lee KK, Veesler D, Bloom JD, King NP. Front Immunol. 2021 Jun 29;12:710263. doi: 10.3389/fimmu.2021.710263. eCollection 2021.

Functional development of a V3/glycan-specific broadly neutralizing antibody isolated from a case of HIV superinfection.  Shipley MM, Mangala Prasad V, Doepker LE, Dingens A, Ralph DK, Harkins E, Dhar A, Arenz D, Chohan V, Weight H, Mandaliya K, Bloom JD, Matsen FA 4th, Lee KK, Overbaugh JM. Elife. 2021 Jul 15;10:e68110. doi: 10.7554/eLife.68110.

Quadrivalent influenza nanoparticle vaccines induce broad protection. Boyoglu-Barnum S, Ellis D, Gillespie RA, Hutchinson GB, Park YJ, Moin SM, Acton OJ, Ravichandran R, Murphy M, Pettie D, Matheson N, Carter L, Creanga A, Watson MJ, Kephart S, Ataca S, Vaile JR, Ueda G, Crank MC, Stewart L, Lee KK, Guttman M, Baker D, Mascola JR, Veesler D, Graham BS, King NP, Kanekiyo M. Nature. 2021 Apr;592(7855):623-628. doi: 10.1038/s41586-021-03365-x. Epub 2021 Mar 24.

Development of antibody-dependent cell cytotoxicity function in HIV-1 antibodies. Doepker LE, Danon S, Harkins E, Ralph DK, Yaffe Z, Garrett ME, Dhar A, Wagner C, Stumpf MM, Arenz D, Williams JA, Jaoko W, Mandaliya K, Lee KK, Matsen FA 4th, Overbaugh JM. Elife. 2021 Jan 11;10:e63444. doi: 10.7554/eLife.63444.

Simple Platform for Automating Decoupled LC-MS Analysis of Hydrogen/Deuterium Exchange Samples. Watson MJ, Harkewicz R, Hodge EA, Vorauer C, Palmer J, Lee KK, Guttman M. J Am Soc Mass Spectrom. 2021 Feb 3;32(2):597-600. doi: 10.1021/jasms.0c00341. Epub 2020 Dec 7.

Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2. Walls AC, Fiala B, Schäfer A, Wrenn S, Pham MN, Murphy M, Tse LV, Shehata L, O’Connor MA, Chen C, Navarro MJ, Miranda MC, Pettie D, Ravichandran R, Kraft JC, Ogohara C, Palser A, Chalk S, Lee EC, Guerriero K, Kepl E, Chow CM, Sydeman C, Hodge EA, Brown B, Fuller JT, Dinnon KH 3rd, Gralinski LE, Leist SR, Gully KL, Lewis TB, Guttman M, Chu HY, Lee KK, Fuller DH, Baric RS, Kellam P, Carter L, Pepper M, Sheahan TP, Veesler D, King NP. Cell. 2020 Nov 25;183(5):1367-1382.e17. doi: 10.1016/j.cell.2020.10.043. Epub 2020 Oct 31.

The influence of proline isomerization on potency and stability of anti-HIV antibody 10E8. Guttman M, Padte NN, Huang Y, Yu J, Rocklin GJ, Weitzner BD, Scian M, Ho DD, Lee KK. Sci Rep. 2020 Aug 31;10(1):14313. doi: 10.1038/s41598-020-71184-7.

Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2. Walls AC, Fiala B, Schäfer A, Wrenn S, Pham MN, Murphy M, Tse LV, Shehata L, O’Connor MA, Chen C, Navarro MJ, Miranda MC, Pettie D, Ravichandran R, Kraft JC, Ogohara C, Palser A, Chalk S, Lee EC, Kepl E, Chow CM, Sydeman C, Hodge EA, Brown B, Fuller JT, Dinnon KH 3rd, Gralinski LE, Leist SR, Gully KL, Lewis TB, Guttman M, Chu HY, Lee KK, Fuller DH, Baric RS, Kellam P, Carter L, Pepper M, Sheahan TP, Veesler D, King NP. bioRxiv. 2020 Aug 12:2020.08.11.247395. doi: 10.1101/2020.08.11.247395. Preprint.

Direct imaging of liquid domains in membranes by cryo-electron tomography. Cornell CE, Mileant A, Thakkar N, Lee KK, Keller SL. Proc Natl Acad Sci U S A. 2020 Aug 18;117(33):19713-19719. doi: 10.1073/pnas.2002245117. Epub 2020 Aug 5.

New Biophysical Approaches Reveal the Dynamics and Mechanics of Type I Viral Fusion Machinery and Their Interplay with Membranes. Benhaim MA, Lee KK. Viruses. 2020 Apr 8;12(4):413. doi: 10.3390/v12040413.

Bridging protein structure, dynamics, and function using hydrogen/deuterium-exchange mass spectrometry. Hodge EA, Benhaim MA, Lee KK. Protein Sci. 2020 Apr;29(4):843-855. doi: 10.1002/pro.3790. Epub 2019 Nov 25.

Prebiotic amino acids bind to and stabilize prebiotic fatty acid membranes. Cornell CE, Black RA, Xue M, Litz HE, Ramsay A, Gordon M, Mileant A, Cohen ZR, Williams JA, Lee KK, Drobny GP, Keller SL. Proc Natl Acad Sci U S A. 2019 Aug 27;116(35):17239-17244. doi: 10.1073/pnas.1900275116. Epub 2019 Aug 12.

Kappa chain maturation helps drive rapid development of an infant HIV-1 broadly neutralizing antibody lineage. Simonich CA, Doepker L, Ralph D, Williams JA, Dhar A, Yaffe Z, Gentles L, Small CT, Oliver B, Vigdorovich V, Mangala Prasad V, Nduati R, Sather DN, Lee KK, Matsen Iv FA, Overbaugh J. Nat Commun. 2019 May 16;10(1):2190. doi: 10.1038/s41467-019-09481-7.

De novo design of tunable, pH-driven conformational changes. Boyken SE, Benhaim MA, Busch F, Jia M, Bick MJ, Choi H, Klima JC, Chen Z, Walkey C, Mileant A, Sahasrabuddhe A, Wei KY, Hodge EA, Byron S, Quijano-Rubio A, Sankaran B, King NP, Lippincott-Schwartz J, Wysocki VH, Lee KK, Baker D. Science. 2019 May 17;364(6441):658-664. doi: 10.1126/science.aav7897.

Deep Mutational Scan of the Highly Conserved Influenza A Virus M1 Matrix Protein Reveals Substantial Intrinsic Mutational Tolerance. Hom N, Gentles L, Bloom JD, Lee KK. J Virol. 2019 Jun 14;93(13):e00161-19. doi: 10.1128/JVI.00161-19. Print 2019 Jul 1.

Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus. Marcandalli J, Fiala B, Ols S, Perotti M, de van der Schueren W, Snijder J, Hodge E, Benhaim M, Ravichandran R, Carter L, Sheffler W, Brunner L, Lawrenz M, Dubois P, Lanzavecchia A, Sallusto F, Lee KK, Veesler D, Correnti CE, Stewart LJ, Baker D, Loré K, Perez L, King NP. Cell. 2019 Mar 7;176(6):1420-1431.e17. doi: 10.1016/j.cell.2019.01.046.

An indirect debiasing method: Priming a target attribute reduces judgmental biases in likelihood estimations. Lee KK. PLoS One. 2019 Mar 7;14(3):e0212609. doi: 10.1371/journal.pone.0212609. eCollection 2019.

Tracking Higher Order Protein Structure by Hydrogen-Deuterium Exchange Mass Spectrometry. Benhaim M, Lee KK, Guttman M. Protein Pept Lett. 2019;26(1):16-26. doi: 10.2174/0929866526666181212165037.