A5007964042- Enzyme Structure and Function
- Protein Structure and Dynamics
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- Alzheimer's disease research and treatments
- Bacterial Genetics and Biotechnology
- Bacteriophages and microbial interactions
- RNA modifications and cancer
- Prion Diseases and Protein Misfolding
- Biochemical and Molecular Research
- Metal-Catalyzed Oxygenation Mechanisms
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Enzyme Production and Characterization
- Electron Spin Resonance Studies
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Genomics and Phylogenetic Studies
- Photosynthetic Processes and Mechanisms
- Amino Acid Enzymes and Metabolism
- Tuberculosis Research and Epidemiology
- Mitochondrial Function and Pathology
- Connexins and lens biology
- Lanthanide and Transition Metal Complexes
- DNA and Nucleic Acid Chemistry
- Porphyrin Metabolism and Disorders
- DNA Repair Mechanisms
University of California, Los Angeles
2016-2025
United States Department of Energy
2017-2024
Digital Proteomics (United States)
2024
Howard Hughes Medical Institute
2013-2023
Genomics (United Kingdom)
2004-2022
UCLA Health
2003-2018
Vehicle Technologies Office
2016
Uniformed Services University of the Health Sciences
2016
University of Dundee
2016
Proteogenomics Research Institute for Systems Medicine
2014
The developing science called structural genomics has focused to date mainly on high-throughput expression of individual proteins, followed by their purification and structure determination. In contrast, the term biology is used denote determination structures, often complexes several macromolecules, that illuminate aspects biological function. Here we bridge with a procedure for determining protein previously unknown function from any organism sequenced genome. From computational genomic...
Nature provides many examples of self- and co-assembling protein-based molecular machines, including icosahedral protein cages that serve as scaffolds, enzymes, compartments for essential biochemical reactions virus capsids, which encapsidate protect viral genomes mediate entry into host cells. Inspired by these natural materials, we report the computational design experimental characterization co-assembling, two-component, 120-subunit nanostructures with weights (1.8 to 2.8 megadaltons)...
Membrane transporters that use energy stored in sodium gradients to drive nutrients into cells constitute a major class of proteins. We report the crystal structure member solute symporters (SSS), Vibrio parahaemolyticus sodium/galactose symporter (vSGLT). The ∼3.0 angstrom contains 14 transmembrane (TM) helices an inward-facing conformation with core inverted repeats 5 TM (TM2 TM6 and TM7 TM11). Galactose is bound center core, occluded from outside solutions by hydrophobic residues....
The voltage-dependent anion channel (VDAC) constitutes the major pathway for entry and exit of metabolites across outer membrane mitochondria can serve as a scaffold molecules that modulate organelle. We report crystal structure beta-barrel eukaryotic protein, murine VDAC1 (mVDAC1) at 2.3 A resolution, revealing high-resolution image its architecture formed by 19 beta-strands. Unlike recent NMR human VDAC1, position voltage-sensing N-terminal segment is clearly resolved. alpha-helix oriented...
Subcellular membraneless assemblies are a reinvigorated area of study in biology, with spirited scientific discussions on the forces between low-complexity protein domains within these assemblies. To illuminate forces, we determined atomic structures five segments from associated Their common structural feature is stacking into kinked β sheets that pair protofilaments. Unlike steric zippers amyloid fibrils, interact weakly through polar atoms and aromatic side chains. By computationally...
Amyloid-beta (Aβ) aggregates are the main constituent of senile plaques, histological hallmark Alzheimer's disease. Aβ molecules form β-sheet containing structures that assemble into a variety polymorphic oligomers, protofibers, and fibers exhibit range lifetimes cellular toxicities. This nature has frustrated its biophysical characterization, structural determination, our understanding pathological mechanism. To elucidate polymorphism in atomic detail, we determined eight new microcrystal...
Abstract Small heat shock proteins alphaA and alphaB crystallin form highly polydisperse oligomers that frustrate protein aggregation, crystallization, amyloid formation. Here, we present the crystal structures of truncated forms bovine (AAC 59–163 ) human (ABC 68–162 ), both containing C‐terminal extension functions in chaperone action oligomeric assembly. In structures, extensions swap into neighboring molecules, creating runaway domain swaps. This interface, termed DS, enables...
Designing protein molecules that will assemble into various kinds of ordered materials represents an important challenge in nanotechnology. We report the crystal structure a 12-subunit cage self-assembles by design to form tetrahedral roughly 16 nanometers diameter. The strategy fusing together oligomeric domains can be generalized produce other cages or extended materials.
Significance We find that the core domain of human molecular chaperone αB-crystallin can function effectively in preventing protein aggregation and amyloid toxicity. The represents only half total sequence protein, but it is one most potent known inhibitors amyloid-β, a process implicated Alzheimer’s disease. have determined high-resolution structures this investigated its biophysical properties solution. excised efficiently prevents thereby reduces toxicity resulting aggregates to cells....
The x-ray crystal structure of a peptide designed to form double-stranded parallel coiled coil shows that it is actually triple-stranded formed by three α-helices. Unlike the coil, helices run up-up-down. stabilized distinctive hydrophobic interface consisting eight layers. As in design, each α-helix contributes one leucine side chain layer. suggests interactions are dominant factor stabilization coils. stoichiometry and geometry coils primarily determined packing solvent-inaccessible...
High resolution (1.43−1.8 Å) crystal structures and the corresponding electron paramagnetic resonance (EPR) spectra were determined for T4 lysozyme derivatives with a disulfide-linked nitroxide side chain [-CH2-S-S-CH2-(3-[2,2,5,5-tetramethyl pyrroline-1-oxyl]) ≡ R1] substituted at solvent-exposed helix surface sites (Lys65, Arg80, Arg119) or tertiary contact site (Val75). In each case, density is clearly resolved disulfide group, revealing distinct rotamers of chain, defined by dihedral...
The traditional site-directed spin labeling (SDSL) method, which utilizes cysteine residues and sulfhydryl-reactive nitroxide reagents, can be challenging for proteins that contain functionally important native or disulfide bonds. To make SDSL amenable to any protein, we introduce an orthogonal strategy, i.e., one does not rely on of the functional groups found in common 20 amino acids. In this genetically encoded unnatural acid p-acetyl-L-phenylalanine (p-AcPhe) is reacted with a...
Abstract The structure of the DNA fluorochrome 4′-6-diamidine-2-phenyl indole (DAPI) bound to synthetic B-DNA oligonucleotide C-G-C-G-A-A-T-T-C-G-C-G has been solved by single crystal x-ray diffraction methods, at a resolution 2.4 Å. is nearly isomorphous with that native molecule alone. With one DAPI and 25 waters per double helix, residual error 21.5% for 2428 reflections above 2-sigma level. inserts itself edgewise into narrow minor groove, displacing ordered spine hydration. water...
The bacterial nucleoid-associated protein Fis regulates diverse reactions by bending DNA and through DNA-dependent interactions with other control proteins enzymes. In addition to dynamic nonspecific binding DNA, forms stable complexes segments that share little sequence conservation. Here we report the first crystal structures of bound high- low-affinity 27-base-pair sites. These 11 reveal selects targets primarily indirect recognition mechanisms involving shape minor groove...
A disulfide-linked nitroxide side chain (R1) is the most widely used spin label for determining protein topology, mapping structural changes, and characterizing nanosecond backbone motions by site-directed labeling. Although internal motion of R1 number preferred rotamers are limited, translating interspin distance measurements spatial orientation information into constraints challenging. Here, we introduce a highly constrained designated RX as an alternative to these applications. formed...
Bacterial microcompartments are a functionally diverse group of proteinaceous organelles that confine specific reaction pathways in the cell within thin protein-based shell. The propanediol utilizing (Pdu) microcompartment contains reactions for metabolizing 1,2-propanediol certain enteric bacteria, including Salmonella. Pdu shell is assembled from few thousand protein subunits several different types. Here we report crystal structures two key proteins, PduA and PduT. offer insights into...
Chromosome-capping enzyme complex Telomeres cap and protect the ends of our chromosomes. The telomerase helps maintain telomere DNA repeat sequences. Telomerase consists an RNA a number protein subunits. Jiang et al. used cryo–electron microscopy x-ray crystallography to determine structure Tetrahymena complex. is made up three subcomplexes, which include two previously unknown subunits in addition seven known structures also reveal path component catalytic core. Science , this issue p....
Significance Ketoreductases are the most commonly used enzymes in industrial pharmaceutical synthesis. We investigated nature of enantioselectivity closely related mutant ketoreductases that reduce almost-symmetrical 3-oxacyclopentanone and 3-thiacyclopentanone, which difficult to enantioselectively by other means. present efficiencies select variants their crystallographic structures. Our experimental theoretical studies reveal how mutations modulate stereoselectivity reduction. Molecular...