A5008723061- Influenza Virus Research Studies
- Protein Structure and Dynamics
- RNA and protein synthesis mechanisms
- Lipid Membrane Structure and Behavior
- Crystallography and molecular interactions
- Receptor Mechanisms and Signaling
- Ion channel regulation and function
- Monoclonal and Polyclonal Antibodies Research
- Electron Spin Resonance Studies
- Spectroscopy and Quantum Chemical Studies
- Cytokine Signaling Pathways and Interactions
- Cardiac electrophysiology and arrhythmias
- Mass Spectrometry Techniques and Applications
- Advanced NMR Techniques and Applications
- ATP Synthase and ATPases Research
- Antimicrobial Peptides and Activities
- Photosynthetic Processes and Mechanisms
- Eicosanoids and Hypertension Pharmacology
- Cardiomyopathy and Myosin Studies
- Veterinary medicine and infectious diseases
- Fuel Cells and Related Materials
- interferon and immune responses
- Liver Disease Diagnosis and Treatment
- Advanced Fluorescence Microscopy Techniques
- Metabolism and Genetic Disorders
University of California, San Francisco
2014-2023
Trinity College Dublin
2020
Peking University
2019
University of Arizona
2019
Swarthmore College
2010-2012
Precise packing for membrane proteins Although nonpolar amino acid side chains pack efficiently in proteins, it has been difficult to determine how much this contributes protein stability. Designed have largely relied on other stabilizing interactions such as metal-ligand and hydrogen bonds. Mravic et al. uncovered a steric code underlying the folding of natural phospholamban, which they used design stable with interfaces. They suggest that residues plays role stability many proteins....
Water-mediated interactions play key roles in drug binding. In protein sites with sparse polar functionality, a small-molecule approach is often viewed as insufficient to achieve high affinity and specificity. Here we show that small molecules can enable potent inhibition by targeting waters. The M2 proton channel of influenza A the target antiviral drugs amantadine rimantadine. Structural studies binding using X-ray crystallography have been limited because challenging nature target, one...
Significance The conduction of protons through the highly restricted paths transmembrane proteins is an essential process living systems and intriguing problem in modern physical chemistry. small size influenza M2 proton channel makes it ideal system for study transport across a membrane. Additionally, has medical relevance as anti-flu drug target. These high-resolution structures were obtained by crystallizing protein membrane-like environment reveal networks hydrogen-bonded waters that...
Significance The influenza M2 channel is among the smallest proton-selective channels found in nature. High-resolution structures of this further our understanding how protons are transported across a membrane bilayer through constricted protein environment. This study also has broader implications for structural interpretation water using X-ray crystallographic techniques. Previous structure determined synchrotron radiation with cryocooling were biased by low temperature, and room...
Higher throughput methods to mount and collect data from multiple small radiation-sensitive crystals are important support challenging structural investigations using microfocus synchrotron beamlines. Furthermore, efficient sample-delivery essential carry out productive femtosecond crystallography experiments at X-ray free-electron laser (XFEL) sources such as the Linac Coherent Light Source (LCLS). To address these needs, a high-density sample grid useful scaffold for both crystal growth...
The M2 protein is a small proton channel found in the influenza A virus that necessary for viral replication. target of class drugs called adamantanes, which block pore and prevent from replicating. In recent decades mutations have arisen adamantanes binding to pore, with most prevalent these being S31N. Here we report first crystal structure S31N mutant crystallized using lipidic cubic phase crystallization techniques solved 1.59 Å resolution. Asn31 residues point directly into center form...
The V27A mutation confers adamantane resistance on the influenza A matrix 2 (M2) proton channel and is becoming more prevalent in circulating populations of virus. We have used X-ray crystallography to determine structures a spiro-adamantyl amine inhibitor bound M2(22–46) also M2(21–61) Inwardclosed conformation. binding site nearly identical for two crystal structures. Compared M2 "wild type" (WT) with valine at position 27, we observe that pore wider its N-terminus as result this removes...
The amantadine-resistant S31N mutant of the influenza A M2 proton channel has become prevalent in currently circulating viruses. Here, we have solved an X-ray crystal structure M2(22–46) that contains two distinct conformational states within its asymmetric unit. This reveals mechanism adamantane resistance both channel. In Inwardopen conformation, Asn31 side chain faces pore and sterically blocks binding site. Inwardclosed forms hydrogen bonds with carbonyls at monomer–monomer interface,...
The influenza A M2 wild-type (WT) proton channel is the target of anti-influenza drug rimantadine. Rimantadine has two enantiomers, though most investigations into binding and inhibition have used a racemic mixture. Solid-state NMR experiments using full length-M2 WT shown significant spectral differences that were interpreted to indicate tighter for (R)- vs (S)-rimantadine. However, it was unclear if this correlates with functional difference in inhibition. Using X-ray crystallography, we...
As a target of antiviral drugs, the influenza A M2 protein has been focus numerous structural studies and extensively explored as model ion channel. In this study, we capitalize on expanding body high-resolution data available for to design interpret site-directed spin-labeling electron paramagnetic resonance spectroscopy experiments drug-induced conformational changes embedded in lipid bilayers. We obtained presence adamantane drugs two different constructs (M2TM 22-46 M2TMC 23-60). M2TM...
The influenza A M2 protein is a 97-residue integral membrane involved in viral budding and proton conductance. Although crystal NMR structures exist of truncated constructs the protein, there disagreement between models only limited structural data are available for full-length protein. Here, structure C-terminal juxtamembrane region (sites 50-60) investigated using site-directed spin-labeling electron paramagnetic resonance (EPR) spectroscopy lipid bilayers. Sites 50-60 were chosen study...
Inhibition of the M2 proton channel in influenza A virus prevents viral replication from occurring.Two four FDA--approved drugs for treatment infections, amantadine and rimantadine, target channel.However, because is a membrane protein, structural studies drug binding to have been limited due challenging nature target.The only previously published drug--bound crystal structure was 3.5 Å resolution [1]; presence pore confirmed by this structure, but orientation could not be unambiguously...