A5053075000- Enzyme Structure and Function
- Protein Structure and Dynamics
- Alzheimer's disease research and treatments
- DNA and Nucleic Acid Chemistry
- Prion Diseases and Protein Misfolding
- Chemical Synthesis and Analysis
- RNA and protein synthesis mechanisms
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Supramolecular Self-Assembly in Materials
- Biochemical and Molecular Research
- Glycosylation and Glycoproteins Research
- Amino Acid Enzymes and Metabolism
- Bacteriophages and microbial interactions
- RNA Research and Splicing
- Enzyme Production and Characterization
- Peptidase Inhibition and Analysis
- Neurological diseases and metabolism
- Computational Drug Discovery Methods
- Photosynthetic Processes and Mechanisms
- Parkinson's Disease Mechanisms and Treatments
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Mass Spectrometry Techniques and Applications
- Advanced Electron Microscopy Techniques and Applications
- RNA modifications and cancer
- Bacterial Genetics and Biotechnology
University of California, Los Angeles
2016-2025
Howard Hughes Medical Institute
2015-2024
UCLA Health
2011-2024
Digital Proteomics (United States)
2024
Genomics (United Kingdom)
2006-2023
United States Department of Energy
2007-2017
Vehicle Technologies Office
2016
University of California, Santa Barbara
2014
Montana State University
2014
Victor Chang Cardiac Research Institute
2011
Plethora of Secretory Amyloids Protein aggregation and the formation amyloids are associated with several dozen pathological conditions in humans, including Alzheimer's disease, Parkinson's type II diabetes. In addition, a few functional amyloid systems known: prions fungi, bacterial protein curli, chorion eggshell silkworm, Pmel-17 involved mammalian skin pigmentation. Now Maji et al. (p. 328 , published online 18 June) propose that endocrine hormone peptides proteins stored an amyloid-like...
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...
The reaction catalyzed by Escherichia coli dihydrofolate reductase (ecDHFR) cycles through five detectable kinetic intermediates: holoenzyme, Michaelis complex, ternary product tetrahydrofolate (THF) binary and THF·NADPH complex. Isomorphous crystal structures analogous to these intermediates the transition state (as represented methotrexate·NADPH complex) have been used assemble a 2.1 Å resolution movie depicting loop subdomain movements during catalytic cycle (see Supporting Information)....
Design and Build Self-assembling biomolecules are attractive building blocks in the development of functional materials. Sophisticated DNA-based materials have been developed; however, progress designing protein-based has slower. King et al. (p. 1171 ) describe a general computational method which protein first symmetrically docked onto target architecture, then binding interfaces that drive self-assembly designed. As proof principle, trimeric were used to design self-assembling 12-subunit...
DNA polymerase beta (pol beta) fills single nucleotide (nt) gaps in produced by the base excision repair pathway of mammalian cells. Crystal structures have been determined representing intermediates 1 nt gap-filling reaction pol beta: binary complex with a gapped substrate (2.4 A resolution), ternary including ddCTP (2.2 A), and product containing only nicked (2.6 A). Upon binding to gap complex, thumb subdomain rotates into closed conformation contact otherwise solvent-exposed...
Two ternary complexes of rat DNA polymerase β (pol β), a template-primer, and dideoxycytidine triphosphate (ddCTP) have been determined at 2.9 Å 3.6 resolution, respectively. ddCTP is the (ddC), nucleoside analog that targets reverse transcriptase human immunodeficiency virus (HIV) present used to treat AIDS. Although crystals two belong different space groups, structures are similar, suggesting polymerase-DNA-ddCTP interactions not affected by crystal packing forces. In pol active site,...
α-Synuclein (aSyn) fibrillar polymorphs have distinct in vitro and vivo seeding activities, contributing differently to synucleinopathies. Despite numerous prior attempts, how polymorphic aSyn fibrils differ atomic structure remains elusive. Here, we present fibril from the full-length recombinant human their capacity cytotoxicity vitro. By cryo-electron microscopy helical reconstruction, determine structures of two predominant species, a rod twister, both at 3.7 Å resolution. Our models...
Amyloid diseases, including Alzheimer's, Parkinson's, and the prion conditions, are each associated with a particular protein in fibrillar form. These amyloid fibrils were long suspected to be disease agents, but evidence suggests that smaller, often transient polymorphic oligomers toxic entities. Here, we identify segment of amyloid-forming αB crystallin, which forms an oligomeric complex exhibiting properties other oligomers: β-sheet-rich structure, cytotoxicity, recognition by...
Structures of the 31-kilodalton catalytic domain rat DNA polymerase β (pol β) and whole 39-kilodalton enzyme were determined at 2.3 3.6 angstrom resolution, respectively. The is composed fingers, palm, thumb subdomains arranged to form a binding channel reminiscent domains Klenow fragment Escherichia coli I, HIV-1 reverse transcriptase, bacteriophage T7 RNA polymerase. amino-terminal 8-kilodalton attached fingers subdomain by flexible hinge. two invariant aspartates found in all sequences...
Bacterial microcompartments are primitive organelles composed entirely of protein subunits. Genomic sequence databases reveal the widespread occurrence across diverse microbes. The prototypical bacterial microcompartment is carboxysome, a shell for sequestering carbon fixation reactions. We report three-dimensional crystal structures multiple carboxysome proteins, revealing hexameric unit as basic building block and showing how these hexamers assemble to form flat facets polyhedral shell....
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...
The carboxysome is a bacterial microcompartment that functions as simple organelle by sequestering enzymes involved in carbon fixation. shell roughly 800 to 1400 angstroms diameter and assembled from several thousand protein subunits. Previous studies have revealed the three-dimensional structures of hexameric proteins, which self-assemble into molecular layers most likely constitute facets polyhedral shell. Here, we report two proteins previously unknown function, CcmL OrfA (or CsoS4A),...
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...
Nature uses a limited set of metabolites to perform all the biochemical reactions. To increase metabolic capabilities biological systems, we have expanded natural network, using nonnatural engineering approach. The branched-chain amino acid pathways are extended produce abiotic longer chain keto acids and alcohols by elongation activity 2-isopropylmalate synthase altering substrate specificity downstream enzymes through rational protein design. When introduced into Escherichia coli, this...
In the rare medical condition termed injection amyloidosis, extracellular fibrils of insulin are observed. We found that segment B-chain with sequence LVEALYL is smallest both nucleates and inhibits fibrillation full-length in a molar ratio–dependent manner, suggesting this central to cross-β spine fibril. isolation from rest protein, forms microcrystalline aggregates fibrillar morphology, structure which we determined 1 Å resolution. The segments stacked into pairs tightly interdigitated...
A crystal structure of human fibrinogen has been determined at approximately 3.3 resolution. The protein was purified from blood plasma, first by a cold ethanol precipitation procedure and then stepwise chromatography on DEAE-cellulose. product obtained that homogeneous SDS-polyacrylamide gels. Nonetheless, when individual crystals used for X-ray diffraction were examined SDS gel electrophoresis after data collection, two species alpha chain present, indicating some proteolysis had occurred...