Group members (left to right): Andrea Flores, Mercedes Spínola, Federico M. Ruiz, Elena Santillana, Irene Davó, Antonio Romero and Javier Medrano.
The Structural Biology of Proteins group focuses on two major research lines (i) the molecular basis of Acinetobacter baumannii infection, a life-threatening pathogen, (ii) the mechanism of carbohydrate recognition by lectins, which are involved in cancer development.
Infectious diseases are the leading cause of death worldwide and are a major challenge for public health. Despite recent advances in biochemical and structural studies of a series of pathogenic factors, a better understanding of targets involved in antibiotic resistance and microbial pathogenesis and how they are transferred is important to combat infectious diseases. Approaches to combat bacterial infection rely on, 1) the disruption of the bacteria growth cycle by preventing the synthesis and assembly of key components of bacterial processes and, 2) by inhibition of virulence traits. Our goal is to better understand the pathogenic mechanisms developed by gram-negative organisms (A. baumannii, P. aeruginosa, ..) in infection, using a structural approach.
MAIN RESEARCH LINES
β-lactamases and bacterial toxin-antitoxin systems. The number of class D carbapenemases identified in hospitals worldwide continues to grow significantly. Most of them have been isolated from gram-negative pathogens. Our more recent efforts attempt to correlate resistance mutations in new subfamilies of oxacillinases for the design of new antimicrobial agents. Furthermore, we are focusing in the structural characterization of the AbkA/AbkB toxin-antitoxin system in A. baumannii, related to virulence and involved in the successful dissemination of plasmids carrying the blaOXA-24/40-like gene, thus contributing to the plasmid stability.
Type VI secretion system (T6SS). Due to the difficulties inherent to this system, we have designed a strategy to address each individual component and subsequent assembly in silico. We have solved the crystal structure of Hcp (TssD) of A. baumannii characterizing the aggregation state by electron microscopy. Policlonal antibodies against Hcp confirmed that the T6SS of A. baumannii is active and functional in the AB0057 strain and in other different nosocomial strains of diverse origins. Very recently, we reported the crystal structure of VgrG1 from P. aeruginosa, TssL and TssK from A. baumannii. Our study reveals several remarkable structural features pointing to the possible roles of the two main segments of VgrG1: the head as a scaffold cargo domain and the β-roll spike with implications in the cell-membrane puncturing process and as a carrier of cognate toxins.
Galectins. Galectins recognize and bind β-galactosides that are present in the great diversity of glycan structures located as glycoconjugates on the cell surface. The recognition and interpretation of the sugar (carbohydrate) code located in these glycoconjugates is carried out by its interaction with proteins, and the reading of this code is essential in a wide range of normal biological processes as well as in the pathogenesis of several human diseases. Galectins are closely related to these pathologies including overexpression in cancerous cells and cancer-associated stromal cells, particularly in those cell types that do not normally express the specific galectin. The final goal of this project is to characterize, structurally and biochemically, the binding properties of human galectins: Gal-1, Gal-3, Gal-4 and Gal-8 to a wide variety of mono- and multivalent glycostructures.
Gato E, Vázquez-Ucha JC, Rumbo-Feal S, Álvarez-Fraga L, Vallejo JA, Martínez-Guitián M, Beceiro A, Ramos Vivas J, Sola Campoy PJ, Pérez-Vázquez M, Oteo Iglesias J, Rodiño-Janeiro BK, Romero A, Poza M, Bou G and Pérez A
PNAS, 117 (29) 17249-1725
. Kpi, a chaperone-usher pili system associated with the worldwide-disseminated high-risk clone Klebsiella pneumoniae ST-15
Ruiz FM, Lopez J, Ferrara CG, Santillana E, Espinosa YR, Feldman MF and Romero A.
J Bacteriol 202(17): e00210-20
. Structural characterization of TssL from Acinetobacter baumannii: a key component of the type VI secretion system
Diercks T, Medrano FJ, FitzGerald FG, Beckwith D, Pedersen MJ, Reihill M, Ludwig A-K, Romero A, Oscarson S, Cudic M and Gabius H-J
Chem. Eur. J. https://doi.org/10.1002/chem.202003143
. Galectin‐Glycan Interaction: Guideline for Monitoring by 77Se NMR Spectroscopy and Solvent (H2O/D2O) Impact on Binding
Marín-Ramos NI, Balabasquer M, Ortega-Nogales FJ, Torrecillas IR, Gil-Ordóñez N, Marcos-Ramiro B, Aguilar-Garrido P, Cushman I, Romero A, Medrano F.J, Gajate C, Mollinedo F, Philips MR, Campillo M, Gallardo M, Martín-Fontecha M, López-Rodríguez ML and Ortega-Gutiérrez S
J Med Chem 62(13), 6035-6046; DOI: 10.1021/acs.jmedchem.9bOO145
. Potent Isoprenylcysteine Carboxylmethyltransferase (ICMT) Inhibitor Improves Survival in Ras-Driven Acute Myeloid Leukemia
Romero A and Gabius H-J
Expert Opin Ther Tar. 23(10), 819-828 https://doi.org/10.1080/14728222.2019.1675638
. Galectin-3: is this member of a large family of multifunctional lectins (already) a therapeutic target?
Campos LA, Sharma R, Alvira S, Ruiz FM, Ibarra-Molero B, Sadqi M, Alfonso C, Rivas G, Sanchez-Ruiz JM, Romero Garrido A, Valpuesta JM, Muñoz V
Nat Commun. 2019 Dec 13;10(1):5703. doi: 10.1038/s41467-019-13686-1
. Engineering protein assemblies with allosteric control via monomer fold-switching
Ludwig, A.-K.*, Michalak, M.*, Xiao, Q.*, Gilles, U.*, Medrano, F.J.*, Ma, H.*, FitzGerald, F.G.*, Hasley, W.D., Melendez-Davila, A., Liu, M., Rahimi, K., Kostina, N.Y., Rodriguez-Emmenegger, C., Möller, M., Lindner, I., Kaltner, H., Cudic, M., Reusch, D., Kopitz, J., Romero, A., Oscarson, S., Klein, M.L., Gabius, H.-J. and Percec, V. . Design-functionality relationships for adhesion/growth-regulatory galectins. PNAS
Flores-Ibarra, A., Vértesy, S., Medrano, F.J., Gabius, H.-J. and Romero, A. . Crystallization of a human galectin-3 variant with two ordered segments in the shortened N-terminal tail. Scientific Reports volume 8, Article number: 9835
Ruiz F.M., Gilles U., Ludwig A.-K., Sehad C., Shiao T.-C., García-Caballero G., Kaltner H., Lindner I., Roy R., Reusch D., Romero A., Gabius, H.-J. . Chicken GRIFIN: Structural characterization in crystals and in solution. Biochimie 146, 127-138
Kopitz J., Xiao Q., Ludwig A.-K., Romero A., Michalak M., Sherman S.E., Zhou X., Dazen C., Vértesy S., Kaltner H., Klein M.L., Gabius H.-J., Percec V. . Reaction of a Programmable Glycan Presentation of Glycodendrimersomes and Cells with Engineered Human Lectins to Show the Sugar Functionality of the Cell Surface. Angew. Chem. Int. Ed. Engl. 56(46), 14677-14681
MINECO (BFU2016-77835-R) (2017-2019)
MINECO (BFU2014-55448-P) (2015-2016)
CM S2010/BMD2353 (2012-2016)
MICINN (BFU2011-24615) (2011-2014)
MICINN CONSOLIDER-INGENIO (CSD2009-00088) (2011-2016)