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A key interaction with RPA orients XPA in NER complexes.
Topolska-Woś AM, Sugitani N, Cordoba JJ, Le Meur KV, Le Meur RA, Kim HS, Yeo JE, Rosenberg D, Hammel M, Schärer OD, Chazin WJ
(2020) Nucleic Acids Res 48: 2173-2188
MeSH Terms: DNA, DNA Damage, DNA Repair, DNA, Single-Stranded, DNA-Binding Proteins, Humans, Magnetic Resonance Spectroscopy, Models, Molecular, Protein Binding, Replication Protein A, Xeroderma Pigmentosum Group A Protein
Show Abstract · Added March 11, 2020
The XPA protein functions together with the single-stranded DNA (ssDNA) binding protein RPA as the central scaffold to ensure proper positioning of repair factors in multi-protein nucleotide excision repair (NER) machinery. We previously determined the structure of a short motif in the disordered XPA N-terminus bound to the RPA32C domain. However, a second contact between the XPA DNA-binding domain (XPA DBD) and the RPA70AB tandem ssDNA-binding domains, which is likely to influence the orientation of XPA and RPA on the damaged DNA substrate, remains poorly characterized. NMR was used to map the binding interfaces of XPA DBD and RPA70AB. Combining NMR and X-ray scattering data with comprehensive docking and refinement revealed how XPA DBD and RPA70AB orient on model NER DNA substrates. The structural model enabled design of XPA mutations that inhibit the interaction with RPA70AB. These mutations decreased activity in cell-based NER assays, demonstrating the functional importance of XPA DBD-RPA70AB interaction. Our results inform ongoing controversy about where XPA is bound within the NER bubble, provide structural insights into the molecular basis for malfunction of disease-associated XPA missense mutations, and contribute to understanding of the structure and mechanical action of the NER machinery.
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
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11 MeSH Terms
Federating Structural Models and Data: Outcomes from A Workshop on Archiving Integrative Structures.
Berman HM, Adams PD, Bonvin AA, Burley SK, Carragher B, Chiu W, DiMaio F, Ferrin TE, Gabanyi MJ, Goddard TD, Griffin PR, Haas J, Hanke CA, Hoch JC, Hummer G, Kurisu G, Lawson CL, Leitner A, Markley JL, Meiler J, Montelione GT, Phillips GN, Prisner T, Rappsilber J, Schriemer DC, Schwede T, Seidel CAM, Strutzenberg TS, Svergun DI, Tajkhorshid E, Trewhella J, Vallat B, Velankar S, Vuister GW, Webb B, Westbrook JD, White KL, Sali A
(2019) Structure 27: 1745-1759
MeSH Terms: Computational Biology, Crystallography, X-Ray, Databases, Protein, Magnetic Resonance Spectroscopy, Models, Molecular, Protein Conformation, Proteins
Show Abstract · Added March 21, 2020
Structures of biomolecular systems are increasingly computed by integrative modeling. In this approach, a structural model is constructed by combining information from multiple sources, including varied experimental methods and prior models. In 2019, a Workshop was held as a Biophysical Society Satellite Meeting to assess progress and discuss further requirements for archiving integrative structures. The primary goal of the Workshop was to build consensus for addressing the challenges involved in creating common data standards, building methods for federated data exchange, and developing mechanisms for validating integrative structures. The summary of the Workshop and the recommendations that emerged are presented here.
Copyright © 2019.
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7 MeSH Terms
Protein structure prediction using sparse NOE and RDC restraints with Rosetta in CASP13.
Kuenze G, Meiler J
(2019) Proteins 87: 1341-1350
MeSH Terms: Computational Biology, Magnetic Resonance Spectroscopy, Models, Molecular, Protein Conformation, Protein Folding, Proteins, Software
Show Abstract · Added March 21, 2020
Computational methods that produce accurate protein structure models from limited experimental data, for example, from nuclear magnetic resonance (NMR) spectroscopy, hold great potential for biomedical research. The NMR-assisted modeling challenge in CASP13 provided a blind test to explore the capabilities and limitations of current modeling techniques in leveraging NMR data which had high sparsity, ambiguity, and error rate for protein structure prediction. We describe our approach to predict the structure of these proteins leveraging the Rosetta software suite. Protein structure models were predicted de novo using a two-stage protocol. First, low-resolution models were generated with the Rosetta de novo method guided by nonambiguous nuclear Overhauser effect (NOE) contacts and residual dipolar coupling (RDC) restraints. Second, iterative model hybridization and fragment insertion with the Rosetta comparative modeling method was used to refine and regularize models guided by all ambiguous and nonambiguous NOE contacts and RDCs. Nine out of 16 of the Rosetta de novo models had the correct fold (global distance test total score > 45) and in three cases high-resolution models were achieved (root-mean-square deviation < 3.5 å). We also show that a meta-approach applying iterative Rosetta + NMR refinement on server-predicted models which employed non-NMR-contacts and structural templates leads to substantial improvement in model quality. Integrating these data-assisted refinement strategies with innovative non-data-assisted approaches which became possible in CASP13 such as high precision contact prediction will in the near future enable structure determination for large proteins that are outside of the realm of conventional NMR.
© 2019 Wiley Periodicals, Inc.
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7 MeSH Terms
Sex differences in anthracycline-induced cardiotoxicity: the benefits of estrogens.
Cadeddu Dessalvi C, Pepe A, Penna C, Gimelli A, Madonna R, Mele D, Monte I, Novo G, Nugara C, Zito C, Moslehi JJ, de Boer RA, Lyon AR, Tocchetti CG, Mercuro G
(2019) Heart Fail Rev 24: 915-925
MeSH Terms: Anthracyclines, Biomarkers, Cardiotonic Agents, Cardiotoxicity, Echocardiography, Female, Gonadal Steroid Hormones, Heart, Heart Failure, Humans, Magnetic Resonance Spectroscopy, Male, Mitochondria, Nuclear Medicine, Oxidative Stress, Prognosis, Reperfusion Injury, Risk Factors, Sex Characteristics
Show Abstract · Added November 12, 2019
Anthracyclines are the cornerstone for many oncologic treatments, but their cardiotoxicity has been recognized for several decades. Female subjects, especially before puberty and adolescence, or after menopause, seem to be more at increased risk, with the prognostic impact of this sex issue being less consistent compared to other cardiovascular risk factors. Several studies imply that sex differences could depend on the lack of the protective effect of sex hormones against the anthracycline-initiated damage in cardiac cells, or on differential mitochondria-related oxidative gene expression. This is also reflected by the results obtained with different diagnostic methods, such as cardiovascular biomarkers and imaging techniques (echocardiography, magnetic resonance, and nuclear medicine) in the diagnosis and monitoring of cardiotoxicity, confirming that sex differences exist. The same is true about protective strategies from anthracycline cardiotoxicity. Indeed, first studied to withstand oxidative damage in response to ischemia/reperfusion (I/R) injury, cardioprotection has different outcomes in men and women. A number of studies assessed the differences in I/R response between male and female hearts, with oxidative stress and apoptosis being shared mechanisms between the I/R and anthracyclines heart damage. Sex hormones can modulate these mechanisms, thus confirming their importance in the pathophysiology in cardioprotection not only from the ischemia/reperfusion damage, but also from anthracyclines, fueling further cardio-oncologic research on the topic.
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19 MeSH Terms
Exploration of New Contrasts, Targets, and MR Imaging and Spectroscopy Techniques for Neuromuscular Disease - A Workshop Report of Working Group 3 of the Biomedicine and Molecular Biosciences COST Action BM1304 MYO-MRI.
Strijkers GJ, Araujo ECA, Azzabou N, Bendahan D, Blamire A, Burakiewicz J, Carlier PG, Damon B, Deligianni X, Froeling M, Heerschap A, Hollingsworth KG, Hooijmans MT, Karampinos DC, Loudos G, Madelin G, Marty B, Nagel AM, Nederveen AJ, Nelissen JL, Santini F, Scheidegger O, Schick F, Sinclair C, Sinkus R, de Sousa PL, Straub V, Walter G, Kan HE
(2019) J Neuromuscul Dis 6: 1-30
MeSH Terms: Animals, Contrast Media, Dog Diseases, Dogs, European Union, Humans, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Muscles, Neuromuscular Diseases
Show Abstract · Added March 3, 2020
Neuromuscular diseases are characterized by progressive muscle degeneration and muscle weakness resulting in functional disabilities. While each of these diseases is individually rare, they are common as a group, and a large majority lacks effective treatment with fully market approved drugs. Magnetic resonance imaging and spectroscopy techniques (MRI and MRS) are showing increasing promise as an outcome measure in clinical trials for these diseases. In 2013, the European Union funded the COST (co-operation in science and technology) action BM1304 called MYO-MRI (www.myo-mri.eu), with the overall aim to advance novel MRI and MRS techniques for both diagnosis and quantitative monitoring of neuromuscular diseases through sharing of expertise and data, joint development of protocols, opportunities for young researchers and creation of an online atlas of muscle MRI and MRS. In this report, the topics that were discussed in the framework of working group 3, which had the objective to: Explore new contrasts, new targets and new imaging techniques for NMD are described. The report is written by the scientists who attended the meetings and presented their data. An overview is given on the different contrasts that MRI can generate and their application, clinical needs and desired readouts, and emerging methods.
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Structural Model of Ghrelin Bound to its G Protein-Coupled Receptor.
Bender BJ, Vortmeier G, Ernicke S, Bosse M, Kaiser A, Els-Heindl S, Krug U, Beck-Sickinger A, Meiler J, Huster D
(2019) Structure 27: 537-544.e4
MeSH Terms: Animals, Binding Sites, COS Cells, Chlorocebus aethiops, Ghrelin, HEK293 Cells, Humans, Magnetic Resonance Spectroscopy, Models, Molecular, Mutagenesis, Site-Directed, Protein Binding, Protein Conformation, Receptors, Ghrelin
Show Abstract · Added March 21, 2020
The peptide ghrelin targets the growth hormone secretagogue receptor 1a (GHSR) to signal changes in cell metabolism and is a sought-after therapeutic target, although no structure is known to date. To investigate the structural basis of ghrelin binding to GHSR, we used solid-state nuclear magnetic resonance (NMR) spectroscopy, site-directed mutagenesis, and Rosetta modeling. The use of saturation transfer difference NMR identified key residues in the peptide for receptor binding beyond the known motif. This information combined with assignment of the secondary structure of ghrelin in its receptor-bound state was incorporated into Rosetta using an approach that accounts for flexible binding partners. The NMR data and models revealed an extended binding surface that was confirmed via mutagenesis. Our results agree with a growing evidence of peptides interacting via two sites at G protein-coupled receptors.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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Response of Secondary Metabolism of Hypogean Actinobacterial Genera to Chemical and Biological Stimuli.
Covington BC, Spraggins JM, Ynigez-Gutierrez AE, Hylton ZB, Bachmann BO
(2018) Appl Environ Microbiol 84:
MeSH Terms: Actinobacteria, Bacterial Proteins, Biological Products, Caves, Genome, Bacterial, Magnetic Resonance Spectroscopy, Metabolomics, Multigene Family, Phylogeny, Polyketides, Secondary Metabolism
Show Abstract · Added March 26, 2019
Microorganisms within microbial communities respond to environmental challenges by producing biologically active secondary metabolites, yet the majority of these small molecules remain unidentified. We have previously demonstrated that secondary metabolite biosynthesis in actinomycetes can be activated by model environmental chemical and biological stimuli, and metabolites can be identified by comparative metabolomics analyses under different stimulus conditions. Here, we surveyed the secondary metabolite productivity of a group of 20 phylogenetically diverse actinobacteria isolated from hypogean (cave) environments by applying a battery of stimuli consisting of exposure to antibiotics, metals, and mixed microbial culture. Comparative metabolomics was used to reveal secondary metabolite responses from stimuli. These analyses revealed substantial changes in global metabolomic dynamics, with over 30% of metabolomic features increasing more than 10-fold under at least one stimulus condition. Selected features were isolated and identified via nuclear magnetic resonance (NMR), revealing several known secondary metabolite families, including the tetarimycins, aloesaponarins, hypogeamicins, actinomycins, and propeptins. One prioritized metabolite was identified to be a previously unreported aminopolyol polyketide, funisamine, produced by a cave isolate of when exposed to mixed culture. The production of funisamine was most significantly increased in mixed culture with species. The biosynthetic gene cluster responsible for the production of funisamine was identified via genomic sequencing of the producing strain, sp. strain KDCAGE35, which facilitated a deduction of its biosynthesis. Together, these data demonstrate that comparative metabolomics can reveal the stimulus-induced production of natural products from diverse microbial phylogenies. Microbial secondary metabolites are an important source of biologically active and therapeutically relevant small molecules. However, much of this active molecular diversity is challenging to access due to low production levels or difficulty in discerning secondary metabolites within complex microbial extracts prior to isolation. Here, we demonstrate that ecological stimuli increase secondary metabolite production in phylogenetically diverse actinobacteria isolated from understudied hypogean environments. Additionally, we show that comparative metabolomics linking stimuli to metabolite response data can effectively reveal secondary metabolites within complex biological extracts. This approach highlighted secondary metabolites in almost all observed natural product classes, including low-abundance analogs of biologically relevant metabolites, as well as a new linear aminopolyol polyketide, funisamine. This study demonstrates the generality of activating stimuli to potentiate secondary metabolite production across diverse actinobacterial genera.
Copyright © 2018 American Society for Microbiology.
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11 MeSH Terms
Exercise is Associated With Increased Small HDL Particle Concentration and Decreased Vascular Stiffness in Rheumatoid Arthritis.
Byram KW, Oeser AM, Linton MF, Fazio S, Stein CM, Ormseth MJ
(2018) J Clin Rheumatol 24: 417-421
MeSH Terms: Aged, Arthritis, Rheumatoid, Blood Pressure, C-Reactive Protein, Cardiovascular Diseases, Cholesterol, HDL, Cross-Sectional Studies, Exercise, Female, Follow-Up Studies, Humans, Incidence, Magnetic Resonance Spectroscopy, Male, Middle Aged, Reference Values, Risk Assessment, Self Report, Severity of Illness Index, Vascular Stiffness
Show Abstract · Added April 10, 2019
OBJECTIVE - Patients with rheumatoid arthritis (RA) have increased cardiovascular (CV) risk. In the general population, exercise improves several CV risk factors. In a cross-sectional study, we examined the hypothesis that more exercise is associated with protective traditional and non-traditional CV risk factor profile in patients with RA.
METHODS - Patient-reported exercise outside of daily activities was quantified by time and metabolic equivalents per week (METmin/week) and CV risk factors including blood pressure, standard lipid profiles, lipoprotein particle concentrations (NMR spectroscopy), and vascular indices were measured in 165 patients with RA. The relationship between exercise and CV risk factors was assessed according to whether patients exercised or not, and after adjustment for age, race and sex.
RESULTS - Over half (54%) of RA patients did not exercise. Among those who did exercise, median value for exercise duration was 113 min/week [IQR: 60, 210], and exercise metabolic equivalent expenditure was 484 METmin/week [IQR: 258, 990]. Disease activity (measured by DAS28 score), C-reactive protein, waist-hip ratio, and prevalence of hypertension were lower in patients who exercised compared to those who did not (all p-values < 0.05) but standard lipid profile and body mass index were not significantly different. Patients who exercised had significantly higher concentrations of HDL particles (p = 0.004) and lower vascular stiffness as measured by pulse wave velocity (p = 0.005).
CONCLUSIONS - More self-reported exercise in patients with RA was associated with a protective CV risk factor profile including lower waist-hip ratio, higher HDL particle concentration, lower vascular stiffness, and a lower prevalence of hypertension.
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20 MeSH Terms
Structure and Function of the Transmembrane Domain of NsaS, an Antibiotic Sensing Histidine Kinase in Staphylococcus aureus.
Bhate MP, Lemmin T, Kuenze G, Mensa B, Ganguly S, Peters JM, Schmidt N, Pelton JG, Gross CA, Meiler J, DeGrado WF
(2018) J Am Chem Soc 140: 7471-7485
MeSH Terms: Anti-Bacterial Agents, Bacitracin, Bacterial Proteins, Gene Knockout Techniques, Histidine Kinase, Hydrophobic and Hydrophilic Interactions, Magnetic Resonance Spectroscopy, Membrane Proteins, Microbial Sensitivity Tests, Molecular Dynamics Simulation, Nisin, Protein Conformation, alpha-Helical, Protein Domains, Staphylococcus aureus
Show Abstract · Added March 21, 2020
NsaS is one of four intramembrane histidine kinases (HKs) in Staphylococcus aureus that mediate the pathogen's response to membrane active antimicrobials and human innate immunity. We describe the first integrative structural study of NsaS using a combination of solution state NMR spectroscopy, chemical-cross-linking, molecular modeling and dynamics. Three key structural features emerge: First, NsaS has a short N-terminal amphiphilic helix that anchors its transmembrane (TM) bundle into the inner leaflet of the membrane such that it might sense neighboring proteins or membrane deformations. Second, the transmembrane domain of NsaS is a 4-helix bundle with significant dynamics and structural deformations at the membrane interface. Third, the intracellular linker connecting the TM domain to the cytoplasmic catalytic domains of NsaS is a marginally stable helical dimer, with one state likely to be a coiled-coil. Data from chemical shifts, heteronuclear NOE, H/D exchange measurements and molecular modeling suggest that this linker might adopt different conformations during antibiotic induced signaling.
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Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations.
Huang H, Kuenze G, Smith JA, Taylor KC, Duran AM, Hadziselimovic A, Meiler J, Vanoye CG, George AL, Sanders CR
(2018) Sci Adv 4: eaar2631
MeSH Terms: Cell Membrane, HEK293 Cells, Humans, KCNQ1 Potassium Channel, Leupeptins, Long QT Syndrome, Loss of Function Mutation, Magnetic Resonance Spectroscopy, Mutant Proteins, Mutation, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Protein Domains, Protein Folding, Protein Structure, Secondary, Proteolysis
Show Abstract · Added March 14, 2018
Mutations that induce loss of function (LOF) or dysfunction of the human KCNQ1 channel are responsible for susceptibility to a life-threatening heart rhythm disorder, the congenital long QT syndrome (LQTS). Hundreds of mutations have been identified, but the molecular mechanisms responsible for impaired function are poorly understood. We investigated the impact of 51 KCNQ1 variants with mutations located within the voltage sensor domain (VSD), with an emphasis on elucidating effects on cell surface expression, protein folding, and structure. For each variant, the efficiency of trafficking to the plasma membrane, the impact of proteasome inhibition, and protein stability were assayed. The results of these experiments combined with channel functional data provided the basis for classifying each mutation into one of six mechanistic categories, highlighting heterogeneity in the mechanisms resulting in channel dysfunction or LOF. More than half of the KCNQ1 LOF mutations examined were seen to destabilize the structure of the VSD, generally accompanied by mistrafficking and degradation by the proteasome, an observation that underscores the growing appreciation that mutation-induced destabilization of membrane proteins may be a common human disease mechanism. Finally, we observed that five of the folding-defective LQTS mutant sites are located in the VSD S0 helix, where they interact with a number of other LOF mutation sites in other segments of the VSD. These observations reveal a critical role for the S0 helix as a central scaffold to help organize and stabilize the KCNQ1 VSD and, most likely, the corresponding domain of many other ion channels.
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16 MeSH Terms