About

Kelly Lee is the Sidney Nelson Endowed Professor in Medicinal Chemistry at the University of Washington. Her research utilizes complementary structural and biophysical methods to characterize conformational changes in viruses during host cell invasion. Her focus is on understanding the transient and dynamic functional states of viral proteins, which are often difficult to study with classical structural techniques. Her core expertise includes Hydrogen/Deuterium-Exchange Mass Spectrometry (HDX-MS), cryo-electron microscopy (cryo-EM), and small-angle X-ray scattering (SAXS) to monitor conformational changes in protein complexes and viruses. Dr. Lee's work involves dissecting the membrane fusion mechanisms of influenza virus hemagglutinin (HA) and HIV Env using cryo-ET, SAXS, and HDX-MS. Her recent studies have visualized fusion protein-mediated membrane remodeling and elucidated the sequence of events necessary for efficient fusion. Supported by NIH and Gates Foundation awards, her lab investigates the structural basis of antigenicity and immunogenicity of HIV Env glycoproteins, analyzing isolate-specific differences and their impact on immune responses. She collaborates with other research groups to study HIV transmission and neutralizing antibody development, contributing significant insights into viral entry mechanisms and immune evasion.

Research topics

• Immunology
• Virology
• Biology
• Chemistry
• Nanotechnology
• Biomedical engineering
• Computational biology
• Genetics
• Materials science
• Physics
• Medicine
• Optics
• Engineering
• Nuclear magnetic resonance
• Biochemistry

Selected publications

• Structure of HIV-1 Env glycoprotein on virions reveals an alternative fusion subunit organization and native membrane coupling

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-10 · 4 citations

  articleOpen accessSenior authorCorresponding

  An effective vaccine for Human Immunodeficiency Virus type-1 (HIV-1) has yet to be developed, and detailed characterization of functional Env glycoprotein, the primary antigenic target on virions, has remained elusive. While engineered Env trimers recapitulate many aspects of functional Env, key differences in antigenicity and dynamic behavior have been reported. Here, cryo-electron tomography and subtomogram averaging of HIV-1 virus-like particles (VLPs) revealed conformational differences in critical membrane-proximal regions compared to soluble Envs. Hydrogen/Deuterium-Exchange Mass Spectrometry and Molecular Dynamics captured dynamic profiles of membrane-bound Env and identified critical interactions with membrane. We show that disruption of the viral membrane results in relaxation of Env to a form that resembles engineered, soluble trimers. Additionally, Env from mature and immature VLPs exhibit only minor conformational differences, while surface clustering on virions changes significantly. These studies provide new insights into the essential role the membrane plays in maintaining Env in its native conformational form.

  PublisherOA PDFDOI

• BPS2026 – Structural dynamics of HIV-1 envelope glycoproteins on virions uncovered by molecular dynamics and cryo-electron tomography

  Biophysical Journal · 2026-02-01

  articleSenior author
  PublisherDOI

• Reconstructing a Missing Link of HIV-1 Assembly: HIV-1 Envelope-Matrix Interactions in a Native Viral Context

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-16 · 1 citations

  articleOpen accessSenior authorCorresponding

  The envelope surface glycoprotein (Env) on HIV-1 drives cell entry and genome delivery through its receptor binding and membrane fusion activities. Incorporation of Env onto assembling virions is governed by its cytoplasmic tail (Env-CT) and the matrix (MA) domain of the PR55Gag (Gag) polyprotein. To better understand how Gag recruits Env onto virions while reducing its antigenic profile by restricting Env copy number to low levels, we used cryo-electron tomography (cryo-ET) and subtomogram averaging combined with molecular dynamics simulations to investigate Env-MA association in intact viral particles. Full-length Env-CT was resolved directly over individual MA trimers in regions of MA lattice discontinuity. We observed that the conserved but enigmatic Kennedy-sequence motif in Env-CT forms a key linkage between Env and MA. Mutational analysis confirmed the impact of specific CT and MA interactions on Env incorporation. Gag maturation released MA lattice restraints on Env, facilitating its clustering and promoting fusion activity.

  PublisherOA PDFDOI

• Unleashing virus structural biology: Probing protein and membrane intermediates in the dynamic process of membrane fusion

  QRB Discovery · 2025-01-01 · 1 citations

  reviewOpen access1st authorCorresponding

  Viruses are highly dynamic macromolecular assemblies. They undergo large-scale changes in structure and organization at nearly every stage of their infectious cycles from virion assembly to maturation, receptor docking, cell entry, uncoating and genome delivery. Understanding structural transformations and dynamics across the virus infectious cycle is an expansive area for research that that can also provide insight into mechanisms for blocking infection, replication, and transmission. Additionally, the processes viruses carry out serve as excellent model systems for analogous cellular processes, but in more accessible form. Capturing and analyzing these dynamic events poses a major challenge for many structural biological approaches due to the size and complexity of the assemblies and the heterogeneity and transience of the functional states that are populated. Here we examine the process of protein-mediated membrane fusion, which is carried out by specialized machinery on enveloped virus surfaces leading to delivery of the viral genome. Application of two complementary methods, cryo-electron tomography and structural mass spectrometry enable dynamic intermediate states in intact fusion systems to be imaged and probed, providing a new understanding of the mechanisms and machinery that drive this fundamental biological process.

  PublisherOA PDFDOI

• Author comment: Unleashing virus structural biology: Probing protein and membrane intermediates in the dynamic process of membrane fusion — R1/PR6

  2025-01-19

  peer-reviewOpen access1st authorCorresponding

  Viruses are highly dynamic macromolecular assemblies. They undergo large-scale changes in structure and organization at nearly every stage of their infectious cycles from virion assembly to maturation, receptor docking, cell entry, uncoating and genome delivery. Understanding structural transformations and dynamics across the virus infectious cycle is an expansive area for research that that can also provide insight into mechanisms for blocking infection, replication, and transmission. Additionally, the processes viruses carry out serve as excellent model systems for analogous cellular processes, but in more accessible form. Capturing and analyzing these dynamic events poses a major challenge for many structural biological approaches due to the size and complexity of the assemblies and the heterogeneity and transience of the functional states that are populated. Here we examine the process of protein-mediated membrane fusion, which is carried out by specialized machinery on enveloped virus surfaces leading to delivery of the viral genome. Application of two complementary methods, cryo-electron tomography and structural mass spectrometry enable dynamic intermediate states in intact fusion systems to be imaged and probed, providing a new understanding of the mechanisms and machinery that drive this fundamental biological process.

  PublisherDOI

• Host Switching Mutations in H5N1 Influenza Hemagglutinin Suppress Site-specific Activation Dynamics

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-06

  preprintOpen accessSenior authorCorresponding

  Increase in the occurrence of human H5N1 spillover infections resulting from dissemination of highly pathogenic avian influenza (HPAI) virus into bird and mammal populations raises concerns about HPAI adapting to become human transmissible. Studies identified hemagglutinin (HA) acid stability and receptor preference as essential traits that shape host tropism. Mutations that increase HA stability and affinity for α-2,6-linked sialic acids have been shown to confer airborne transmissibility in a ferret model, however mechanisms of activation of H5 subtype HA have not been probed and the effect of adaptive mutations on HA function has been largely inferred from static structures. Here, we use hydrogen/deuterium-exchange mass spectrometry to dissect activation dynamics for two ancestral HPAI H5 HA, their matched HA with adaptive mutations, and a contemporary H5 HA. By measuring dynamics, we identify variation in active site flexibility among the HA and demonstrate that adaptive mutations result in suppression of fusion peptide dynamics and stabilization of a key subunit interface involved in activation. The contemporary H5 isolated from a recent human spillover case exhibits a relatively protected fusion peptide and moderately depressed pH of activation compared to the HAs examined in this study. Our studies of activation dynamics in the H5 HAs in conjunction with prior analysis of H1 and H3 HA reveal subtype-specific patterns that correlate with adaptive mutation sites and indicate underlying physical constraints on influenza HA adaptation.

  PublisherOA PDFDOI

• Interprotomer Crosstalk in Mosaic Viral Glycoprotein Trimers Provides Insight into Polyvalent Immunogen Co-assembly

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-23

  preprintOpen accessSenior authorCorresponding

  SARS-CoV-2 variants have demonstrated the ability to evade immune responses, leading to waves of infection throughout the pandemic. In response, bivalent mRNA vaccines, encoding the original Wuhan-Hu-1 and emerging variants, were developed to display both spike antigens. To date, it has not been determined whether co-transfection and co-translation of different SARS-CoV-2 variants results in co-assembly of mosaic heterotrimer antigens and how this may affect trimer stability, dynamics, and antigenicity. Understanding whether such mosaic heterotrimers can form and their implications for antigen structure can provide important information to guide future polyvalent vaccine design where multiple variants of an antigen are co-formulated. To investigate this, we purified mosaic spike assemblies of both genetically close (Omicron BA.2 and XBB) and distant (Omicron BA.2 and Wuhan-Hu-1 G614) strains. We found that the stability and integrity of mosaic spike trimers were maintained without misfolding or aggregation. Glycosylation profiles likewise were preserved relative to the homotrimer counterparts. Hydrogen/deuterium-exchange mass spectrometry and biolayer-interferometry were used to investigate the mosaic spike dynamics and any impact on epitope presentation and receptor binding. The Omicron-XBB heterotrimer, sharing a common fusion subunit sequence, retained protomer-specific dynamics similar to the corresponding homotrimers in antigenically important regions. The Omicron-G614 heterotrimer, co-assembling from protomers of divergent fusion subunit sequences, likewise showed overall similar dynamics and conformations in the receptor-binding subunit compared to the homotrimers. However, the incorporation of the Wuhan-Hu-1 G614 protomer led to a stabilizing effect on the relatively unstable Omicron fusion subunit in the heterotrimer. These findings reveal structural dynamic crosstalk in mosaic trimers, suggesting a potential for enhanced immunogen display and important considerations to be aware of in the use of polyvalent nucleic acid vaccines.

  PublisherOA PDFDOI

• A Comparative Analysis of Pre-Advanced Pharmacy Practice Experience Domain Achievement During Introductory Pharmacy Practice Experiences

  American Journal of Pharmaceutical Education · 2025-11-01

  articleOpen accessSenior author
  PublisherDOI

• <i>tert</i>-Butyl Carbonate as a Nucleophile in Epoxide Ring Opening: A Cascade Synthesis of 5-(Hydroxymethyl)oxazolidin-2-one

  The Journal of Organic Chemistry · 2025-06-04 · 5 citations

  articleOpen access1st author

  We report an efficient and scalable synthesis of 5-(hydroxymethyl)oxazolidin-2-ones using tert-butyl carbonate as a nucleophile in a Boc2O-mediated epoxide ring-opening cascade. Optimization identified Et3N as key to high yields, with electron-withdrawing aryl groups further enhancing efficiency (up to 91%). Mechanistic studies support the nucleophilic role of tert-butyl carbonate. This versatile method enables access to pharmaceutically relevant compounds, including intermediates for Linezolid, highlighting its value in medicinal chemistry.

  PublisherDOI

• BPS2025 - Structural dynamics study on mosaic spike heterotrimer provides insights into polyvalent vaccine immunogen display

  Biophysical Journal · 2025-02-01

  articleSenior author
  PublisherDOI

Recent grants

• Structure, dynamics and variation in influenza hemagglutinin-driven fusion

  NIH · $427k · 2012–2016

• Structure, dynamics and variation in influenza hemagglutinin-driven fusion

  NIH · $3.1M · 2012–2023

• NIH Grant R21AI112389

  NIH · $471k · 2017

• Structural and dynamic traits underlying phenotypic variation in HIV-1 Env

  NIH · $2.7M · 2019–2025

• NIH Grant R00GM080352

  NIH · $740k · 2012

Frequent coauthors

• Miklós Guttman

  University of Washington

  39 shared

• Jesse D. Bloom

  Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa

  25 shared

• Vidya Mangala Prasad

  Indian Institute of Science Bangalore

  23 shared

• Rogier W. Sanders

  Cornell University

  22 shared

• Julie Overbaugh

  Fred Hutch Cancer Center

  17 shared

• Neil P. King

  University of Washington

  16 shared

• John R. Mascola

  15 shared

• Ian A. Wilson

  Scripps Research Institute

  15 shared

Labs

• UW Biological Physics, Structure and DesignPI

Awards & honors

• Center for AIDS Research Creative and Novel Ideas in HIV Res…