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The protein complex formed by the Ca2+ sensor NCS-1 and the guanine exchange factor Ric8a co-regulates in a antagonistic manner synapse number and probability of neurotransmitter release, emerging as a potential therapeutic target for diseases affecting synapses such as Fragile X syndrome (FXS), the most common heritable autism disorder. By combining crystallographic and chemoinformatic methodologies, a new and small phenothiazine derivative has been found to inhibit this protein complex, whose contact surface is big and complex. The administration of the compound reduces the aberrant excess of synapse number to normal levels and improves associative learning in a Drosophila FXS model. Finally, the structure-function studies have demonstrated the mechanism of action of this new molecule. This work opens the path to the generation of new drugs to treat neuronal diseases affecting synapse function, such as Autism or Alzheimer.
This work has been carried out by researchers from three CSIC Institutes (Instituto de Química-Física “Rocasolano”, Instituto Cajal and Centro de Investigaciones Biológicas) and the BSRC “Alexander Fleming” in Greece.
Alicia Mansilla, Antonio Chaves-Sanjuan, Nuria E. Campillo, Ourania Semelidou, Loreto Martínez-González, Lourdes Infantes, Juana María González-Rubio, Carmen Gil, Santiago Conde, Efthimio M. C. Skoulaki, Alberto Ferrús, Ana Martínez, María José Sánchez-Barrena. “Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome”. Proc. Nat. Acad. Sci., PNAS (2017).
doi:10.1073/pnas.1611089114
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CSIC press release
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A complex link exists between cell-wall recycling/repair and the manifestation of resistance to β-lactam antibiotics in many Enterobacteriaceae and Pseudomonas aeruginosa. This process is mediated by specific cell-wall-derived muropeptide products. These muropeptides are internalized into the cytoplasm and bind to the transcriptional regulator AmpR, which controls the cytoplasmic events that lead to expression of β-lactamase, an antibiotic-resistance determinant. By a combination of X-ray crystallography, mass spectrometry and molecular dynamics techniques we have characterized the effector-binding domain (EBD) of AmpR. Our results provide insights on the muropeptides triggering antibiotics resistance and revises the dogma in the field.
This is part of a collaborative effort between the IQFR and the Univ. of Notre Dame (Indiana, USA).
Dik, D.A.; Domínguez-Gil, T.; Lee, M.; Hesek, D.; Byun, B.; Fishovitz, J.; Boggess, B.; Hellman, L.M.; Fisher, J. F.; Hermoso, J.A.; Mobashery, S. “Muropeptide Binding and the X-Ray Structure of the Effector Domain of the Transcriptional Regulator AmpR of Pseudomonas aeruginosa”. J. Am. Chem. Soc. (2017).
doi:10.1021/jacs.6b12819
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We study thermochemical [1] and electronic properties [2] of halogen-containing species with relevance to several atmospherical processes (e.g. catalytic ozone destruction and air quality).
On the one hand, we found that Gn (Gaussian-n, n = 3,4) ab initio computations are accurate theoretical methods to provide reliable heat of formation and carbon-halogen bond-energy values of a wide variety of chlorinated and brominated organic species [1]. These data will be implemented in climate models in order to evaluate the atmospheric-impact of these compounds.
On the other hand, we have shown that the CASPT2 methodology ("Complete Active Self Consistent Field Perturbation Theory”) is also an excellent method for providing reliable values of absorption optical parameters (within the UV-Vis range) of representative species such as IBr and HgBr2 which have particular connotation in photochemical atmospheric processes [2].
[1] J.Z. Dávalos, R. Notario, C.A. Cuevas, J.M. Oliva, A. Saiz-Lopez: “Thermochemistry of halogen-containing organic compounds with influence on atmospheric chemistry”. Comp. Theor. Chem. 1099 (2017) 36-44. DOI:10.1016/j.comptc.2016.11.009
[2] S.P. Sitkiewicz, J.M. Oliva, J.Z. Dávalos, R. Notario, A. Saiz-Lopez, D.R. Alcoba, O.B. Oña, D. Roca-Sanjuán; “Ab initio quantum-chemical computations of the electronic states in HgBr2 and IBr: Molecules of interest on the Earth's atmosphere”. J. Chem. Phys. 145 (2016) 244304, 1-14. DOI:10.1063/1.4971856
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Alejandro Manjavacas Arévalo, a former PhD student at the IQFR, has been distinguished with the Young Investigator 2016 prize, granted jointly by the Spanish Physical Royal Society and the BBVA Foundation.
Dr Manjavaca, now at the New Mexico University (USA) as Associated Investigator, carried out his PhD research on “Light-matter interactions at nano-level” at this Institute, under the supervision of Prof. J. García Abajo. His doctoral dissertation, together with that of Dr. Luis Cerdán also from the IQFR, was distinguished with the “Premio Extraordinario 2012-2013” by the Complutense University of Madrid.
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Alfonso Saiz-Lopez, Research Scientist at CSIC and Head of the Link to the ERC press release in this Institute, has obtained an ERC Consolidator Grant 2016 funded with 2 M euros by the European Research Council for the 5-year project “Climate dimension of natural halogens in the Earth system: Past, present, future (CLIMAHAL)”.
Through an extremely competitive selection process, the ERC Consolidator Grants will fund 314 projects (24 in Spain) out of 2300 applications. The CLIMAHAL project will use a multidisciplinary approach including spectroscopic and kinetic methods, and theoretical modelling to determine for the first time how natural halogen molecules affect the climate of our planet in past, present and future scenarios.
The ERC Consolidator Grants open every year to support research of consolidated and exceptional scientists of any nationality and age. The ERC selects pioneering and high risk projects with ground-breaking ideas within their fields of research.
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In the radio program released on 10.10.2016, current aspects of computational chemistry, from quantum chemistry to modeling of biochemical systems have been discussed. Scientific issues in the chemistry of boron have also been mentioned, from new materials to biological aspects, related to this particular element. Recent activities of the "Julio Palacios" Chair, as well as the work carried out by the IQFR library on the updating of the Chair website with scientific, academic, and bibliographic documentation of Julio Palacios, were also described..
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Magnetite is the material used to track the history of the Earth magnetic field. Thus its magnetism, and especially its changes with temperature, have attracted a long-standing interest. Magnetite undergoes several phase transitions, some purely magnetic, like the spin-reorientation transition (typically at 130-140K) where the magnetization changes direction, and others, like the Verwey transition, a metal-insulator transition due to a change in the crystal structure, from cubic to monoclinic. We have recently employed novel microscopy techniques to observe the changes of magnetic domains due to these transitions: one, spin-polarized low-energy electron microscopy (SPLEEM), of which there are four instruments in the world, in collaboration with Andreas K. Schmid and coworkers from the Berkeley National Laboratory, and the other, spin-resolved photoemission electron microscopy (spin-PEEM), of which there is currently only one instrument, at the Max Planck Insitute for Microstructure Physics (Halle), in collaboration with Christian Tusche. Upper left-hand figure: SPLEEM image of the magnetic domains below the Verwey temperature, color-coded for the orientation of the magnetization as shown in the circle below (1). Right-hand figure: spin-PEEM image (2) of the magnetization above (upper image) and below (lower image) the Verwey temperature. These techniques allowed us to obtain images with nm resolution of the magnetic domains below and above the transition temperature.
(1) Laura Martín-García, Arantzazu Mascaraque, Beatriz M. Pabón, Roland Bliem, Gareth S. Parkinson, Gong Chen (陈宫), Andreas K. Schmid, and Juan de la Figuera, "Spin reorientation transition on magnetite (001)", Phys. Rev. B 93 (2016) 134419, DOI:10.1103/PhysRevB.93.134419
(2) J. de la Figuera and C. Tusche, "The Verwey transition observed by spin-resolved photoemission electron microscopy", App. Surf. Sci. (2016), DOI:10.1016/j.apsusc.2016.05.140
