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The assembly platform FimD is required to obtain the most stable quaternary structure of type 1 pili
Type 1 pili are crucial cell surface bacterial virulence factors. Here, the authors show that FimD is required to assemble the most stable quaternary pilus structure by ensuring that the resulting protein polymer is free of structural defects.
- Dawid S. Zyla
- , Thomas Wiegand
- & Rudi Glockshuber
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Probing altered receptor specificities of antigenically drifting human H3N2 viruses by chemoenzymatic synthesis, NMR, and modeling
Binding modes of antigenically drifted hemagglutinins of human influenza A viruses have been determined by NMR using synthetic N-glycans having 13C-labeled monosaccharides to pinpoint which monosaccharides of extended LacNAc chains engage with the HAs.
- Luca Unione
- , Augustinus N. A. Ammerlaan
- & Geert-Jan Boons
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Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue
The accumulation of alpha-synuclein fibrils within neurons is the defining feature of Lewy body dementia (LBD). Here the authors report a method to produce large quantities of alpha-synuclein fibrils that reproduce the complex structure of the fibrils that accumulate in LBD brain tissue.
- Dhruva D. Dhavale
- , Alexander M. Barclay
- & Paul T. Kotzbauer
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Widespread extracellular electron transfer pathways for charging microbial cytochrome OmcS nanowires via periplasmic cytochromes PpcABCDE
How do cells put electrons to rest? Using a minimal pathway to get rid of excess metabolic electrons, diverse environmentally important microbes overcome large spatial, kinetic, and thermodynamic barriers in order to survive in extreme anoxic conditions.
- Pilar C. Portela
- , Catharine C. Shipps
- & Nikhil S. Malvankar
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In-cell NMR suggests that DNA i-motif levels are strongly depleted in living human cells
I-Motifs (iM) are non-canonical DNA structures potentially forming in the accessible, single stranded, cytosine-rich genomic region, but the specific contributions of several factors involved in their formation are unknown. Using in-cell NMR, the authors examined DNA i-motif formation in human cells at body temperature, suggesting i-M occur in a small portion (<1%) of genomic sites predisposed to its formation.
- Pavlína Víšková
- , Eva Ištvánková
- & Lukáš Trantírek
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A structural and dynamic visualization of the interaction between MAP7 and microtubules
Integrated structural data show that the MAP7 microtubule binding domain stabilizes the microtubule lattice through binding along protofilaments. Both strong and weak interactions between MAP7 and the lattice extend beyond a single tubulin dimer and include the tubulin C-terminal tails.
- Agnes Adler
- , Mamata Bangera
- & Marc Baldus
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Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions
Here, the authors show that pathogenic mutations in the polyalanine expansions of PHOX2B promote nascent structural conformations that trigger irreversible phase transitions that arrest wild-type PHOX2B, disrupting function.
- Rosa Antón
- , Miguel Á. Treviño
- & Javier Oroz
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Large dynamics of a phase separating arginine-glycine-rich domain revealed via nuclear and electron spins
The authors show the RNA-induced droplet formation by a component of Cajal bodies and reveal the large nanoseconds mobility of glycine residues inside droplets as a molecular factor potentially contributing to the large dynamics of Cajal bodies.
- Giuseppe Sicoli
- , Daniel Sieme
- & Nasrollah Rezaei-Ghaleh
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DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2
The function of transcription factors is conveyed through intrinsically disordered regions (IDRs) containing activation or repression domains, but the lack of quantitative structural ensemble models prevents their mechanistic decoding. Here, the authors use several methods to demonstrate that DNA binding can lead to complex changes in the IDR ensemble and accessibility on the example of the C-terminal IDR of pioneer factor Sox2.
- Sveinn Bjarnason
- , Jordan A. P. McIvor
- & Pétur O. Heidarsson
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Binding kinetics drive G protein subtype selectivity at the β1-adrenergic receptor
The authors show G protein subtype selectivity at the β1-adrenergic receptor is driven by the binding kinetics of ternary complex formation. Bound to G protein, the receptor adopts conformations that differ from its agonist-bound solution states.
- Andrew J. Y. Jones
- , Thomas H. Harman
- & Daniel Nietlispach
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Cryo-EM structures of lipidic fibrils of amyloid-β (1-40)
Alzheimer’s plaques contain a high amount of Aβ fibrils and a high concentration of lipids. The authors determined structures of Aβ40 fibrils grown in the presence of lipids, revealing high-resolution details of potentially disease-relevant fibril-lipid interactions.
- Benedikt Frieg
- , Mookyoung Han
- & Gunnar F. Schröder
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Disordered regions in proteusin peptides guide post-translational modification by a flavin-dependent RiPP brominase
Here the authors use NMR, SAXS and MD simulations to characterise the structure of proteusin peptides, which are atypically long RiPP substrates. They show a small, unstructured region in the proteusin leader is sufficient for its interaction with a halogenase that brominates the terminal tryptophan residue.
- Nguyet A. Nguyen
- , F. N. U. Vidya
- & Vinayak Agarwal
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The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12
Here, the authors utilise an integrative approach to characterise the fuzzy heterocomplex between CXCL12 and the fully reduced alarmin HMGB1, highlighting the importance of HMGB1’s acidic IDR to the interaction and with cell surface CXCR4.
- Malisa Vittoria Mantonico
- , Federica De Leo
- & Giovanna Musco
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Molecular-level architecture of Chlamydomonas reinhardtii’s glycoprotein-rich cell wall
Chlamydomonas reinhardtii produces a glycoprotein-rich cell wall. Using nuclear magnetic resonance and mass spectrometry approaches, this study reveals unprecedented details on its protein and carbohydrate content, and provide an atomic-level architecture model.
- Alexandre Poulhazan
- , Alexandre A. Arnold
- & Isabelle Marcotte
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Identification of potential aggregation hotspots on Aβ42 fibrils blocked by the anti-amyloid chaperone-like BRICHOS domain
This study identifies potential aggregation hotspots on the fibril surface of Alzheimer’s disease associated Aβ42 fibrils, which are blocked by the anti-amyloid chaperone-like domain BRICHOS.
- Rakesh Kumar
- , Tanguy Le Marchand
- & Axel Abelein
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Origin of the multi-phasic quenching dynamics in the BLUF domains across the species
Here the authors combine 19 F NMR and femtosecond transient absorption to characterise the structural origin of the multiphasic quenching dynamics in various species of BLUF domains, highlighting the importance of the heterogeneous active-site H-bond network.
- Yalin Zhou
- , Siwei Tang
- & Dongping Zhong
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Molecular switching in transcription through splicing and proline-isomerization regulates stress responses in plants
Transcription factor DREB2A interacts with Med25 to regulate stress responses. Here, the authors show that DREB2A uses splicing and proline-isomerization for this regulation and that proline cis-trans switching introduces structural frustration facilitating regulator exchange.
- Frederik Friis Theisen
- , Andreas Prestel
- & Karen Skriver
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Disordered-to-ordered transitions in assembly factors allow the complex II catalytic subunit to switch binding partners
Here, the authors investigate the maturation of human respiratory Complex II, uncovering two metastable intermediates of maturation which suggest changes in intrinsic disorder ensure that the assembly steps occur in the correct sequence.
- Pankaj Sharma
- , Elena Maklashina
- & T. M. Iverson
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Ton motor conformational switch and peptidoglycan role in bacterial nutrient uptake
Gram-negative bacteria rely on the Ton system for nutrient uptake. Here, authors uncover how the ExbD protein acts as a conformational switch and the function of peptidoglycan in order to energize this transport process across the outer membrane.
- Maximilian Zinke
- , Maylis Lejeune
- & Nadia Izadi-Pruneyre
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Competition between inside-out unfolding and pathogenic aggregation in an amyloid-forming β-propeller
Here, the relationship between unfolding and amyloid aggregation of glaucoma-associated myocilin is probed, showing that myocilin is not at equilibrium and pathogenic aggregation competes directly with unfolding.
- Emily G. Saccuzzo
- , Mubark D. Mebrat
- & Raquel L. Lieberman
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An RNA excited conformational state at atomic resolution
Excited conformation state of biomolecule is transient and high-energy conformation state. Here the authors use NMR spectroscopy and computational modeling to reveal the 3D structure of HIV-1 TAR RNA excited conformational state.
- Ainan Geng
- , Laura Ganser
- & Hashim M. Al-Hashimi
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Conformational plasticity of RAS Q61 family of neoepitopes results in distinct features for targeted recognition
The authors use an integrative structural biology approach to elucidate molecular features of the RAS Q61 family of public tumor antigens. This information can be used to develop targeted therapeutics to combat a range of cancers.
- Andrew C. McShan
- , David Flores-Solis
- & Nikolaos G. Sgourakis
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Unravelling the mechanism of neurotensin recognition by neurotensin receptor 1
GPCRs include inactive and active states. 19F-NMR and stopped-flow fluorescence kinetic assays reveal that neurotensin activates the prototypical peptide-binding GPCR, neurotensin receptor 1, through an induced-fit mechanism, where ligand binding precedes receptor conformational changes.
- Kazem Asadollahi
- , Sunnia Rajput
- & Paul R. Gooley
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Distinct activation mechanisms of β-arrestin-1 revealed by 19F NMR spectroscopy
The molecular basis for the functional versatility of β-arrestins in the G-protein coupled receptor signaling pathway is not well understood. Here, the authors use19F NMR spectroscopy to show that different binding partners activate β-arrestin-1 through distinct mechanisms.
- Ruibo Zhai
- , Zhuoqi Wang
- & Yunfei Hu
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Unexpected dynamics in femtomolar complexes of binding proteins with peptides
High binding affinities are usually obtained when ligands are rigidified. Here the authors present flexible peptides binding to Armadillo repeat proteins with femtomolar affinity. They demonstrate that the bound state is characterized by residual dynamics limiting entropic losses upon binding.
- Stefano Cucuzza
- , Malgorzata Sitnik
- & Oliver Zerbe
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Myr-Arf1 conformational flexibility at the membrane surface sheds light on the interactions with ArfGAP ASAP1
An integrated approach combing solution and solid-state NMR, molecular dynamics simulations and neutron reflectometry is applied to characterize dynamic membrane bound forms of ADP-ribosylation factor 1 (Arf1).
- Yue Zhang
- , Olivier Soubias
- & R. Andrew Byrd
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Structural characterization of tin in toothpaste by dynamic nuclear polarization enhanced 119Sn solid-state NMR spectroscopy
Stannous fluoride (SnF2) is a common fluoride source and antimicrobial agent used in commercial toothpaste products. Here, the authors show how dynamic nuclear polarization can be used to perform 119Sn nuclear magnetic resonance spectroscopy experiments that probe the molecular structure of tin ions in commercial toothpastes.
- Rick W. Dorn
- , Scott L. Carnahan
- & Aaron J. Rossini
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Mechanism of selective recognition of Lys48-linked polyubiquitin by macrocyclic peptide inhibitors of proteasomal degradation
Macrocyclic peptides were recently discovered as potent modulators of ubiquitin-mediated cellular signaling pathways. Here the authors used multidisciplinary approach to uncover how macrocyclic peptides that inhibit proteasomal degradation selectively recognize long Lys48-linked polyubiquitin chains.
- Betsegaw Lemma
- , Di Zhang
- & David Fushman
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Structural adaptation of fungal cell wall in hypersaline environment
Solid-state NMR snapshots of Aspergillus sydowii and other halophilic fungal species reveal the structural rearrangement of polysaccharides and proteins, which create a thick, stiff and hydrophobic cell wall to withstand external stress and thrive in hypersaline environment
- Liyanage D. Fernando
- , Yordanis Pérez-Llano
- & Tuo Wang
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DNAJB6 mutants display toxic gain of function through unregulated interaction with Hsp70 chaperones
Here the authors characterize DNAJB6 mutants found in LGMDD1 patients. They show that these mutants retain aggregation-prevention activity, but have impaired regulation of Hsp70 binding, uncontrollably recruiting Hsp70s, depleting the chaperone levels and disrupting proteostasis.
- Meital Abayev-Avraham
- , Yehuda Salzberg
- & Rina Rosenzweig
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DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress
Proximity between mitochondria and endoplasmic reticulum regulates mitochondria fitness and is adversely affected by tissue ischemia. This work reveals that Diaphanous1-Mitofusin2 interaction regulates this proximity and impairs recovery in ischemia.
- Gautham Yepuri
- , Lisa M. Ramirez
- & Ravichandran Ramasamy
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Multivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density
Cognitive impairment in Alzheimer’s disease is associated with Tau at the postsynapse. We show that multivalent Tau interactions arrest in vitro condensates and clusters mimicking the postsynaptic density that may result in synaptic dysfunction.
- Zheng Shen
- , Daxiao Sun
- & Markus Zweckstetter
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Recognition and coacervation of G-quadruplexes by a multifunctional disordered region in RECQ4 helicase
In this work, the authors report a three-step charge-driven coacervation model involving dynamic complexes between a positively charged IDR of human RECQ4 and G-quadruplexes. The IDR also interacts with Replication Protein A, implying RECQ4’s regulatory role.
- Anna C. Papageorgiou
- , Michaela Pospisilova
- & Konstantinos Tripsianes
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Staphylococcus aureus sacculus mediates activities of M23 hydrolases
In this work, the authors provide structural insights into the interaction of two evolutionarily related peptidoglycan hydrolases, lysostaphin and LytM with S. aureus sacculus, and propose a model in which PG crosslinking affects their activity differently.
- Alicja Razew
- , Cedric Laguri
- & Jean-Pierre Simorre
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Integrative solution structure of PTBP1-IRES complex reveals strong compaction and ordering with residual conformational flexibility
An integrated structural biology approach is utilized to elucidate the solution structure of the polypyrimidine-tract binding protein 1 (PTBP1/hnRNP I) complexed with an internal ribosome entry site (IRES) RNA fragment from encephalomyocarditis virus (EMCV).
- Georg Dorn
- , Christoph Gmeiner
- & Frédéric H.-T. Allain
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| Open Access
Driving forces behind phase separation of the carboxy-terminal domain of RNA polymerase II
The condensation of RNA polymerase II (Pol II) into transcriptionally active clusters is critical for eukaryotic gene regulation and pre-mRNA transcription. Here the authors show that a tight network of tyrosine-proline interactions imparts temperature and concentration-dependent self-coacervation of Pol II’s C-terminal domain (CTD).
- David Flores-Solis
- , Irina P. Lushpinskaia
- & Markus Zweckstetter
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Acetylation discriminates disease-specific tau deposition
The authors show that acetylation enhances the aggregation of 3R tau, while blocking the aggregation of 4R tau, providing a molecular basis for disease- and isoform-specific tau deposition.
- Pijush Chakraborty
- , Gwladys Rivière
- & Markus Zweckstetter
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Discovery of a selective and biologically active low-molecular weight antagonist of human interleukin-1β
Interleukin-1β is a pro-inflammatory cytokine of medical importance. Here the authors describe the discovery of a low-molecular weight compound that antagonizes hIL-1β function in cells, demonstrating the relevance of this discovery for future development of hIL-1β directed therapeutics.
- Ulrich Hommel
- , Konstanze Hurth
- & Frédéric Bornancin
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Multifaceted membrane interactions of human Atg3 promote LC3-phosphatidylethanolamine conjugation during autophagy
Here, Ye et al use high-resolution NMR in conjunction with in vitro and in vivo assays to show the catalytically important C-terminal regions of human Atg3 are conformationally dynamic and directly interact with the membrane, in collaboration with its N-terminal membrane curvature-sensitive helix.
- Yansheng Ye
- , Erin R. Tyndall
- & Fang Tian
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Molecular basis of RNA-binding and autoregulation by the cancer-associated splicing factor RBM39
RBM39 is an essential splicing factor for several cancer cells. Here, the authors described how RBM39 selects RNA at atomic level and autoregulates at the mRNA level by selecting the 3’-splice site of a poison exon.
- Sébastien Campagne
- , Daniel Jutzi
- & Frédéric H-T. Allain
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Article
| Open Access
Dynamically regulated two-site interaction of viral RNA to capture host translation initiation factor
RNA viruses use elements of their genomic RNA to commandeer the host translational machinery. Here, the authors use NMR and cryo-EM to reveal the sophisticated strategy by which a viral RNA engages host translational factors in a dynamically regulated two-site interaction.
- Shunsuke Imai
- , Hiroshi Suzuki
- & Ichio Shimada
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Article
| Open Access
Identifying and preventing degradation in flavin mononucleotide-based redox flow batteries via NMR and EPR spectroscopy
Aqueous organic redox-flow batteries are known to suffer capacity loss via degradation of the redox-active species. Here, the authors use in situ methods to study the electrolyte flavin mononucleotide, identifying a redox mediator mechanism that mitigates capacity loss and a route to prevent its degradation.
- Dominic Hey
- , Rajesh B. Jethwa
- & Clare P. Grey
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| Open Access
Atomic-level structure determination of amorphous molecular solids by NMR
The atomic-level ensemble structure of an amorphous form of a drug is determined by combining NMR experiments with molecular dynamics simulations and machine-learned chemical shifts. The structure explains the stabilization of the amorphous form.
- Manuel Cordova
- , Pinelopi Moutzouri
- & Lyndon Emsley
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| Open Access
SHARPER-DOSY: Sensitivity enhanced diffusion-ordered NMR spectroscopy
Since its discovery, the sensitivity of Nuclear Magnetic Resonance has increased steadily. Here the authors report on a liquid-state NMR methodology that increases the sensitivity of the diffusion coefficient measurements 10–100- fold, allowing to use microgram quantities of compounds, while reducing the measurement time to few minutes.
- George Peat
- , Patrick J. Boaler
- & Dušan Uhrín
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| Open Access
Molecular basis of β-lactam antibiotic resistance of ESKAPE bacterium E. faecium Penicillin Binding Protein PBP5
Penicillin Binding Proteins (PBPs) are the main targets of β-lactam antibiotics. Here the authors use NMR spectroscopy, crystallography and microbiology to define the dynamics of E. faecium PBP5 in solution and show that increased acyl-enzyme hydrolysis correlates with increased resistance.
- Yamanappa Hunashal
- , Ganesan Senthil Kumar
- & Wolfgang Peti
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| Open Access
Structural basis for specific RNA recognition by the alternative splicing factor RBM5
The RNA binding protein RBM5 regulates alternative splicing of genes implicated in cancer. Here the authors show structural mechanisms how multiple RNA binding domains of RBM5 cooperate to recognize specific target RNA sequences.
- Komal Soni
- , Pravin Kumar Ankush Jagtap
- & Michael Sattler
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| Open Access
Cytochrome c lysine acetylation regulates cellular respiration and cell death in ischemic skeletal muscle
The authors report that acetylation of cytochrome c on K39 acts as a molecular switch in ischemic skeletal muscle, but not other tissues, to increase respiration and prevent apoptosis. This gives skeletal muscle robust resilience to ischemia and ischemia-reperfusion injury.
- Paul T. Morse
- , Gonzalo Pérez-Mejías
- & Maik Hüttemann
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| Open Access
AI-designed NMR spectroscopy RF pulses for fast acquisition at high and ultra-high magnetic fields
Here, the authors utilized an evolutionary algorithm and artificial intelligence to design new basic 2D biomolecular NMR experiments to accelerate the acquisition of large biomolecular spectra. The method enables recording the spectra of poorly soluble or unstable macromolecules and analyzing the kinetics of biomolecular aggregation and oligomerization. The authors laid the foundation for accelerating multidimensional NMR experiments at high and ultra-high magnetic fields.
- V. S. Manu
- , Cristina Olivieri
- & Gianluigi Veglia
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| Open Access
Multinuclear 1D and 2D NMR with 19F-Photo-CIDNP hyperpolarization in a microfluidic chip with untuned microcoil
The main limitations in NMR techniques are low sensitivity and the requirement for complex instrumentation. Here the authors show that a microfluidic chip with a single untuned planar spiral microcoil, combined with laser-light induced hyperpolarization, allows for multidimensional and heteronuclear Nuclear Magnetic Resonance spectroscopy on picomole quantities of material.
- M. Victoria Gomez
- , Sander Baas
- & Aldrik H. Velders
Modulation of peroxisomal import by the PEX13 SH3 domain and a proximal FxxxF binding motif