A5089406511- HIV Research and Treatment
- Protein Structure and Dynamics
- Bacteriophages and microbial interactions
- HIV/AIDS drug development and treatment
- Enzyme Structure and Function
- RNA and protein synthesis mechanisms
- Advanced Electron Microscopy Techniques and Applications
- Viral Infections and Outbreaks Research
- Lipid Membrane Structure and Behavior
- Hepatitis B Virus Studies
- Mass Spectrometry Techniques and Applications
- Viral gastroenteritis research and epidemiology
- Advanced NMR Techniques and Applications
- Bacterial Genetics and Biotechnology
- Nuclear Structure and Function
- Biochemical and Molecular Research
- Plant Virus Research Studies
- Chromosomal and Genetic Variations
- RNA Interference and Gene Delivery
- Genomics and Phylogenetic Studies
- Spectroscopy and Quantum Chemical Studies
- Microtubule and mitosis dynamics
- Signaling Pathways in Disease
- Cytomegalovirus and herpesvirus research
- HIV-related health complications and treatments
University of Delaware
2017-2025
University of Illinois Urbana-Champaign
2013-2023
University of Pittsburgh
2018-2022
Los Alamos National Laboratory
2021
Johns Hopkins University
2009-2014
Johns Hopkins Medicine
2009-2013
Universidad Nacional de Colombia
2004
Abstract Human immunodeficiency virus type 1 (HIV-1) infection is highly dependent on its capsid. The capsid a large container, made of ∼1,300 proteins with altogether 4 million atoms. Although the are all identical, they nevertheless arrange themselves into largely asymmetric structure hexamers and pentamers. number degrees freedom lack symmetry pose challenge to studying chemical details HIV Simulations over 64 atoms for μs allow us conduct comprehensive study chemical–physical properties...
Abstract The host cell factor cyclophilin A (CypA) interacts directly with the HIV-1 capsid and regulates viral infectivity. Although crystal structure of CypA in complex N-terminal domain protein (CA) has been known for nearly two decades, how modulates infectivity remains unclear. We determined cryoEM assembled at 8-Å resolution. exhibits a distinct CypA-binding pattern which selectively bridges CA hexamers along direction highest curvature. EM-guided all-atom molecular dynamics...
The hepatitis B virus capsid represents a promising therapeutic target. Experiments suggest the must be flexible to function; however, structure and dynamics have not been thoroughly characterized in absence of icosahedral symmetry constraints. Here, all-atom molecular simulations are leveraged investigate without bias, enabling study flexibility its implications for biological function cryo-EM resolution limits. Simulation results confirm reveal propensity asymmetric distortion. capsid’s...
Chemotactic responses in bacteria require large, highly ordered arrays of sensory proteins to mediate the signal transduction that ultimately controls cell motility. A mechanistic understanding molecular events underlying signaling, however, has been hampered by lack a high-resolution structural description extended array. Here, we report novel reconstitution array, involving receptor signaling domain, histidine kinase CheA, and adaptor protein CheW, as well density map core-signaling unit...
Cytoplasmic mislocalization of the TAR-DNA binding protein 43 kDa (TDP-43) leads to large, insoluble aggregates that are a hallmark amyotrophic lateral sclerosis and frontotemporal dementia. Here, we study how importin α1/β recognizes TDP-43 bipartite nuclear localization signal (NLS). We find NLS makes extensive contacts with α1, especially at minor NLS-binding site. results in steric clashes C terminus α1 disrupts N-terminal domain (NTD) dimerization interface. A putative phosphorylation...
Increasing evidence has suggested that the HIV-1 capsid enters nucleus in a largely assembled, intact form. However, not much is known about how cone-shaped interacts with nucleoporins (NUPs) nuclear pore for crossing complex. Here, we elucidate NUP153 binds by engaging assembled protein (CA) lattice. A bipartite motif containing both canonical and noncanonical interaction modules was identified at C-terminal tail region of NUP153. The cargo-targeting phenylalanine-glycine (FG) engaged CA...
HIV-1 infection requires passage of the viral core through nuclear pore cell, a process that depends on functions capsid. Recent studies have shown cores enter nucleus prior to capsid disassembly. Interactions with complex are necessary but not sufficient for entry, and mechanism by which traverses comparably sized is unknown. Here we show highly elastic this property linked entry infectivity. Using atomic force microscopy-based approaches, found purified wild type rapidly returned their...
Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) is a key enzyme in the global carbon cycle, catalyzing CO 2 fixation during photosynthesis. To overcome Rubisco's inherent catalytic inefficiency, many photosynthetic organisms have evolved -concentrating mechanisms. Central to these mechanisms pyrenoid, protein-dense organelle within chloroplast of eukaryotic algae, which increases local concentration around Rubisco and thereby enhances its efficiency. Although structure has been...
Significance The mechanisms of how Cyclophilin A (CypA) regulates HIV-1 infectivity remain poorly understood. We examined the role dynamics in capsid (CA) protein assemblies by magic-angle-spinning NMR. assembled CA is highly dynamic. Dipolar tensors calculated from molecular trajectories are quantitative agreement with NMR results. Motions CypA loop sequence-dependent and attenuated escape mutants A92E G94D. Dynamics similar CA/CypA complex. These findings suggest that escapes dependence...
Virus capsids are protein shells that package the viral genome. Although their morphology and biological functions can vary markedly, often play critical roles in regulating infection pathways. A detailed knowledge of virus capsids, including dynamic structure, interactions with cellular factors, specific they replication cycle, is imperative for development antiviral therapeutics. The following Perspective introduces an emerging area computational biology focuses on dynamics capsid–protein...
HIV-1 uses the microtubule network to traffic viral capsid core toward nucleus. Viral nuclear trafficking and infectivity require kinesin-1 adaptor protein FEZ1. Here, we demonstrate that FEZ1 directly interacts with specifically binds (CA) hexamers. contains multiple acidic, poly-glutamate stretches interact positively charged central pore of CA The FEZ1-capsid interaction competes nucleotides inositol hexaphosphate (IP6) bind at same location. In addition, all-atom molecular dynamic (MD)...
Reverse transcription, an essential event in the HIV-1 life cycle, requires deoxynucleotide triphosphates (dNTPs) to fuel DNA synthesis, thus requiring penetration of dNTPs into viral capsid. The central cavity capsid protein (CA) hexamer reveals itself as a plausible channel that allows passage assembled capsids. Nevertheless, molecular mechanism nucleotide import remains unknown. Employing all-atom dynamics (MD) simulations, we established cooperative binding between nucleotides inside CA...
High-resolution cryoET structures of native HIV-1 capsid in complex with IP6 and CypA are enabled by viral membrane perforation.
HIV-1 maturation inhibitors (MIs), Bevirimat (BVM) and its analogs interfere with the catalytic cleavage of spacer peptide 1 (SP1) from capsid protein C-terminal domain (CACTD), by binding to stabilizing CACTD-SP1 region. MIs are under development as alternative drugs augment current antiretroviral therapies. Although promising, their mechanism action associated virus resistance pathways remain poorly understood at molecular, biochemical, structural levels. We report atomic-resolution...
Maturation of HIV-1 particles encompasses a complex morphological transformation Gag via an orchestrated series proteolytic cleavage events. A longstanding question concerns the structure C-terminal region CA and peptide SP1 (CA-SP1), which represents intermediate during maturation virus. By integrating NMR, cryo-EM, molecular dynamics simulations, we show that in CA-SP1 tubes assembled vitro, represent features assembly state maturation, exists dynamic helix-coil equilibrium, addition...
CryoEM structure of MxB tubes at 4.6 Å resolution reveals novel interfaces responsible for assembly and anti–HIV-1 activity.
The host factor protein TRIM5α plays an important role in restricting the range of HIV-1, interfering with integrity HIV-1 capsid. TRIM5 triggers antiviral innate immune response by functioning as a capsid pattern recognition receptor, although precise mechanism which restriction is imposed not completely understood. Here we used integrated magic-angle spinning nuclear magnetic resonance and molecular dynamics simulations approach to characterize, at atomic resolution, capsid's hexameric...