A5023388531- Protein Structure and Dynamics
- Enzyme Structure and Function
- Advanced NMR Techniques and Applications
- Molecular spectroscopy and chirality
- Mass Spectrometry Techniques and Applications
- RNA and protein synthesis mechanisms
- GNSS positioning and interference
- Advanced MRI Techniques and Applications
- Prostate Cancer Treatment and Research
- Photosynthetic Processes and Mechanisms
- Genetics, Bioinformatics, and Biomedical Research
- Protein Kinase Regulation and GTPase Signaling
- Radio Wave Propagation Studies
- NMR spectroscopy and applications
- Ionosphere and magnetosphere dynamics
- Plant nutrient uptake and metabolism
- Electron Spin Resonance Studies
- Radio Astronomy Observations and Technology
- Various Chemistry Research Topics
- Microbial Metabolic Engineering and Bioproduction
- Earthquake Detection and Analysis
- Antenna Design and Optimization
- RNA modifications and cancer
- Ubiquitin and proteasome pathways
- Cancer-related gene regulation
Scripps Research Institute
2012-2025
Scripps Institution of Oceanography
2021
Ambry Genetics (United States)
2019
Institute for Research in Biomedicine
2010-2018
Institute for Research in Biomedicine
2018
Universitat Politècnica de Catalunya
2011-2014
University of Cambridge
2007-2010
Institució Catalana de Recerca i Estudis Avançats
2010
Institut Curie
2009
Inserm
2009
Long-range correlated motions in proteins are candidate mechanisms for processes that require information transfer across protein structures, such as allostery and signal transduction. However, the observation of backbone correlations between distant residues has remained elusive, only local have been revealed using residual dipolar couplings measured by NMR spectroscopy. In this work, we experimentally identified characterized collective spanning four β-strands separated up to 15 Å...
Significance Most proteins are inherently flexible and their dynamics play a central role in biological functions. A molecular level understanding of protein function mechanism requires an accurate description the atomic coordinates both time space. Here we show, through studies enzyme dihydrofolate reductase, that multiconformer models derived from room-temperature X-ray crystallographic data can be used synergistically with nuclear magnetic resonance relaxation measurements to provide...
Castration-resistant prostate cancer is the lethal condition suffered by patients that become refractory to androgen deprivation therapy. EPI-001 a recently identified compound active against this modulates activity of receptor, nuclear receptor essential for disease progression. The mechanism which exerts its inhibitory however not yet fully understood. Here we show, using high resolution solution magnetic resonance spectroscopy, selectively interacts with partially folded region...
Abstract Many in silico predictors of genetic variant pathogenicity have been previously developed, but there is currently no standard application these algorithms for assessment. Using 4,094 ClinVar-curated missense variants clinically actionable genes, we evaluated the accuracy and yield benign deleterious evidence 5 meta-predictors, as well agreement SIFT PolyPhen2, report derived thresholds best performing predictor(s). REVEL BayesDel outperformed all other meta-predictors (CADD,...
A good combination: The lifetime of interconversion among the ground states a protein ensemble representation could only be assigned to time window that is four orders magnitude large and ranges from 4 ns 50 μs. By combining temperature-dependent NMR relaxation dispersion (RD) experiments dielectric (DR) spectroscopy in solution, was now identified value (10±9) μs at 309 K. Detailed facts importance specialist readers are published as "Supporting Information". Such documents peer-reviewed,...
Disulfide bond protein A (DsbA) plays a pivotal role in catalysing the formation of disulfide bonds within periplasm most Gram-negative bacteria. As this process is required for folding multiple virulence-associated proteins, inhibitors DsbA have potential to be developed as novel anti-virulence agents. Despite extensive efforts develop high-affinity targeting canonical substrate-binding site, success has been limited. In current work, we describe dynamics-driven fragment discovery approach....
Residual dipolar couplings (RDCs) are unique probes of the structural and dynamical properties biomolecules on sub-millisecond time scale that can be used as restraints in ensemble molecular dynamics simulations to study relationship between macromolecular motion biological function. To date, however, this powerful strategy is applicable only molecules do not undergo shape changes sampled by RDCs, thus preventing key macromolecules such multidomain unstructured proteins. In work, we...
The enzyme dihydrofolate reductase (DHFR, E) from Escherichia coli is a paradigm for the role of protein dynamics in catalysis. Previous studies have shown that progresses through kinetic cycle by modulating dynamic conformational landscape presence substrate (DHF), product tetrahydrofolate (THF), and cofactor (NADPH or NADP(+)). This study focuses on quantitative description relationship between fluctuations release, rate-limiting step DHFR NMR relaxation dispersion measurements millisecond...
The small G proteins RalA/B have a crucial function in the regulatory network that couples extracellular signals with appropriate cellular responses. are an important component of Ras signaling pathway and, addition to their role membrane trafficking, implicated initiation and maintenance tumorigenic transformation human cells. RalA RalB share 85% sequence identity collaborate supporting cancer cell proliferation but markedly different effects. is mediating proliferation, while depletion...
Water has a profound effect on the dynamics of biomolecules and governs many biological processes, leading to concept that function is slaved solvent within surrounding biomolecule. Protein conformational changes μs-ms time scales are frequently associated with protein function, but little known about behavior protein-bound water these scales. Here we have used NMR relaxation dispersion measurements probe tryptophan indoles in enzyme dihydrofolate reductase (DHFR). We find during structural...
The rate-determining step in the catalytic cycle of E. coli dihydrofolate reductase is tetrahydrofolate (THF) product release, which can occur via an allosteric or intrinsic pathway. pathway, becomes accessible when reduced cofactor NADPH bound, involves transient sampling a higher energy conformational state, greatly increasing dissociation rate as compared to pathway that obtains absent. Although kinetics this process are known, enzyme structure and THF conformation transiently formed...
Abstract Protein dynamics occurring on a wide range of timescales play crucial role in governing protein function. Particularly, motions between the globular rotational correlation time ( ) and 40 μs (supra‐ window), strongly influence molecular recognition. This supra‐ window was previously hidden, owing to lack experimental methods. Recently, we have developed high‐power relaxation dispersion (RD) experiment for measuring kinetics as fast 4 μs. For first time, this method, performed under...
Abstract Nuclear magnetic resonance spectroscopy (NMR) and molecular dynamics (MD) simulations are powerful techniques for the structural characterization of macromolecules. NMR is unique in its ability to provide experimental information at atomic level on structure as well amplitude rate fluctuations. MD provides physically sound models potential mechanisms that connect conformations time. Nevertheless, none these allow yet obtaining experimentally validated movies protein motions...
Abstract Although serine proteases are found ubiquitously in both eukaryotes and prokaryotes, they comprise the largest of all peptidase families, their dynamic motions remain obscure. The backbone dynamics coagulation protease, apo-thrombin (S195M-thrombin), were compared to substrate-bound form (PPACK-thrombin). R 1 , 2 15 N-{ H}NOEs, relaxation dispersion NMR experiments measured capture across ps ms timescale. ps-ns not significantly altered upon substrate binding. data revealed that is...
Correlated inter-domain motions in proteins can mediate fundamental biochemical processes such as signal transduction and allostery. Here we characterize at structural level the coupling a multidomain enzyme, Adenylate Kinase (AK), using computational methods that exploit shape information encoded residual dipolar couplings (RDCs) measured under steric alignment by nuclear magnetic resonance (NMR). We find experimental evidence for multi-state equilibrium distribution along opening/closing...
This report describes a test of the reality and practical importance long distance HF propagation in which multiple successive reflections from F layer take place. Such modes are launched recovered by appropriate tilts. In this westbound transmissions at various high frequencies Okinawa were received both Mediterranean area island Guam, 2250 km southeast very nearly on same great circle. It is shown that times when signals inaudible Europe they readily audible Guam via path over...
The synchronization of native state motions as they transition between microstates influences catalysis kinetics, mediates allosteric interactions, and reduces the conformational entropy proteins. However, it has proven difficult to describe because are usually minimally frustrated may interconvert on micro- millisecond time scale. Direct observation concerted equilibrium fluctuations would therefore be an important tool for describing protein states. Here we propose a strategy that relates...
An experimental ionospheric sounder has been constructed for vertical-incidence or oblique sounding in the frequency range 600 kHz to 2 MHz. The equipment employs an FM linear sweep transmission generated by direct synthesis from a standard; identical is used demodulation at receiver. Sounding records, made night over 2000-km path, exhibit 10-μs resolution and show no interference broadcast stations. Radiated power ranged 25 250 watts. advantage of good time delay resolution, together with...