Biomolecular NMR: Structure and dynamics of proteins and protein complexes
Miquel Pons
Group Leader
Professor (Organic Chemistry Dept. - UB)
Office Tel : +34 93 403 46 83 / +34 93 403 92 54
Lab Tel : +34 93 403 46 77 / +34 93 403 71 32
e-mail : miquel.pons
irbbarcelona.org
Background
Rapidly changing protein-protein interactions play a key role in regulatory processes. These interactions have to be weak in order to be dynamic. This field of study is particularly challenging because it implies the characterisation of equilibria between free and bound forms. It is also an opportunity because these weak interactions can be successfully targeted by drugs.
Research Interests
We use NMR and other biophysical methods, molecular biology techniques, and computational approaches to study the principles of regulatory interactions between macromolecules.
Research Lines
Kinases and phosphatases involved in signalling pathways. We are currently studying the role of the intrinsically disordered Unique domain of human c-Src, a non-receptor protein tyrosine kinase involved in a large variety of signalling cascades. This domain is responsible for the specificity between members of the c-Src kinase family. We are also working with low molecular weight tyrosine phosphatases that reverse the action of kinases. In particular, we have focused on the contribution of the weak self-association of phosphatases to their regulation and the effects of macromolecular crowding inside the cell.
Nucleoid-associated proteins and the regulation of bacterial pathogenicity. The bacterial symbiotic community is necessary for human health but bacteria can also represent a serious threat, especially because of increased resistance to antibiotics. The enterobacteriaceae group includes pathogens of the genus Yersinia, Salmonella, Escherichia, among others. The success of these pathogens is linked to their capacity to selectively regulate horizontally acquired genes, which include the major sources of virulence and antibiotic resistance. Nucleoid-associated proteins are responsible for this selective regulation. A complete understanding of this process would offer the possibility to develop a sustainable strategy to fight infectious diseases by preventing the manifestation of virulence without the extensive use of antibiotics.
Exploiting the richness of chemical space for drug design. The PubChem collection exceeds 26 million compounds. Given its size, this database offers an ideal opportunity to find useful drug candidates; however, the screening of such a large number of compounds is a challenge. With the aim to increase search efficiency, we are exploring the concept of chemical space to identify functional relationships between molecules. Using LINGO methods, developed in our group, we are building the “yellow pages” of PubChem by grouping molecules with expected similar biological functional properties. This computational approach provides a highly efficient and general virtual screening strategy and is complemented with experimental methods.
Methodology. As the reference group of the Spanish National Large Scale NMR facility located in Barcelona, we actively contribute to the development and implementation of new NMR methodology. In particular, members of the group are working in Dynamic Nuclear Polarization and the combined use of NMR and Small Angle X-ray Scattering.
Funding
This group receives financial support from the following sources:
- Ministerio de Educación y Ciencia (Spanish Ministry of Science and Education)
- Generalitat de Catalunya (Government of Catalonia)
- Fundació Marató de TV3
- European Science Foundation
More info
Biomolecular NMR: Structure and dynamics of proteins and protein complexes
The dimeric structure and the bivalent recognition of H3K4me3 by the tumor suppressor ING4 suggests a mechanism for enhanced targeting of the HBO1 complex to chromatin
Palacios A, Moreno A, Oliveira BL, Rivera T, Prieto J, García P, Fernández-Fernández MR, Bernadó P, Palmero I and Blanco FJ
J Mol Biol, 396 (4), 1117-1127 (2010)
Effect of interdomain dynamics on the structure determination of modular proteins by small-angle scattering
Bernadó P
Eur Biophys J, 39 (5), 769-780 (2010)
N9L and L9N mutations toggle Hha binding and hemolysin regulation by Escherichia coli and Vibrio cholerae H-NS
García J, Madrid C, Cendra M, Juárez A and Pons M
FEBS Lett, 583 (17), 2911-2916 (2009)
Structural characterization of alpha-synuclein in an aggregation prone state
Cho MK, Nodet G, Kim HY, Jensen MR, Bernado P, Fernandez CO, Becker S, Blackledge M and Zweckstetter M
Protein Sci, 18 (9), 1840-1846 (2009)
Quantitative determination of the conformational properties of partially folded and intrinsically disordered proteins using NMR dipolar couplings
Jensen MR, Markwick PR, Meier S, Griesinger C, Zweckstetter M, Grzesiek S, Bernadó P and Blackledge M
Structure, 17 (9), 1169-1185 (2009)
Dynamic interactions of proteins in complex networks: a more structured view
Stein A, Pache RA, Bernadó P, Pons M and Aloy P
FEBS J, 276 (19), 5390-5405 (2009)
A self-consistent description of the conformational behavior of chemically denatured proteins from NMR and small angle scattering
Bernadó P and Blackledge M
Biophys J, 97 (10), 2839-2845 (2009)
Differential regulation of horizontally acquired and core genome genes by the bacterial modulator H-NS
Baños RC, Vivero A, Aznar S, García J, Pons M, Madrid C and Juárez A
PLoS Genet, 5 (6), e1000513 (2009)
Weak oligomerization of low-molecular-weight protein tyrosine phosphatase is conserved from mammals to bacteria
Blobel J, Bernadó P, Xu H, Jin C and Pons M
FEBS J, 276 (16), 4346-4357 (2009)
Structural characterization of the natively unfolded N-terminal domain of human c-Src kinase: insights into the role of phosphorylation of the unique domain
Pérez Y, Gairí M, Pons M and Bernadó P
J Mol Biol, 391 (1), 136-148 (2009)
Structural characterization of unphosphorylated STAT5a oligomerization equilibrium in solution by small-angle x-ray scattering
Bernadó P, Pérez Y, Blobel J, Fernández-Recio J, Svergun DI and Pons M
Prot Sci, 18 (4), 716-726 (2009)
Low-resolution structures of transient protein-protein complexes using small-angle X-ray scattering
Blobel J, Bernadó P, Svergun DI, Tauler R and Pons M
J Am Chem Soc, 131 (12), 4378-4386 (2009)
ProtSA: a web application for calculating sequence specific protein solvent accessibilities in the unfolded ensemble
Estrada J, Bernadó P, Blackledge M and Sancho J
BMC Bioinformatics, 10, 104 (2009)
An improved scoring function for suboptimal polar ligand complexes
Cincilla G, Vidal D and Pons M
J Comput Aided Mol Des, 23 (3), 143-152 (2009)
Uroporphyrinogen III synthase mutations related to congenital erythropoietic porphyria identify a key helix for protein stability
Fortian A, Castaño D, Ortega G, Laín A, Pons M and Millet O
Biochemistry, 48 (2), 454-461 (2009)
Low molecular weight spies of protein-protein interactions
Blobel J, Fayos R, García J, Marimon O, Pérez Y and Pons M
Comptes Rendus Chimie, 11 (4-5), 499-505 (2008)
Structural characterization of the active and inactive states of Src kinase in solution by small-angle X-ray scattering
Bernadó P, Pérez Y, Svergun DI and Pons M
J Mol Biol, 376 (2), 492-505 (2008)
A single residue mutation in Hha preserving structure and binding to H-NS results in loss of H-NS mediated gene repression properties
Cordeiro TN, Garcia J, Pons JI, Aznar S, Juárez A and Pons M
FEBS Lett, 582 (20), 3139-3144 (2008)
Domain conformation of tau protein studied by solution small-angle X-ray scattering
Mylonas E, Hascher A, Bernadó P, Blackledge M, Mandelkow E and Svergun DI
Biochemistry, 47 (39), 10345-10353 (2008)
Interaction of human complement with Sbi, a staphylococcal immunoglobulin-binding protein: indications of a novel mechanism of complement evasion by Staphylococcus aureus
Burman JD, Leung E, Atkins KL, O'Seaghdha MN, Lango L, Bernadó P, Bagby S, Svergun DI, Foster TJ, Isenman DE and van den Elsen JM
J Biol Chem, 283 (25), 17579-17593 (2008)
New perspectives in small-angle scattering to study unstructured states of proteins. In Protein Misfolding
Bernadó P and Svergun DI
Nova Science Publishers. O'Doherty CB and Byrne AC (Ed.) (2008)
Structural relationships among the ribosomal stalk proteins from the three domains of life
Grela P, Bernadó P, Svergun D, Kwiatowski J, Abramczyk D, Grankowski N and Tchórzewski M
J Mol Evol, 67 (2), 154-167 (2008)
Nomen est omen: quantitative prediction of molecular properties directly from IUPAC names
Thormann M, Vidal D, Almstetter M and Pons M
The Open Appl Inform J, 1 (5), 28-32 (2007)
Amino acid bulkiness defines the local conformations and dynamics of natively unfolded alpha-synuclein and tau
Cho MK, Kim HY, Bernado P, Fernandez CO, Blackledge M and Zweckstetter M
J Am Chem Soc, 129 (11), 3032-3033 (2007)
Molecular evolution of the H-NS protein: interaction with Hha-like proteins is restricted to enterobacteriaceae
Madrid C, García J, Pons M and Juárez A
J Bacteriol, 189 (1), 265-268 (2007)
Influence of the Hofmeister anions on protein stability as studied by thermal denaturation and chemical shift perturbation
Tadeo X, Pons M and Millet O
Biochemistry, 46 (3), 917-923 (2007)
The novel Hha/YmoA family of nucleoid-associated proteins: use of structural mimicry to modulate the activity of the H-NS family of proteins
Madrid C, Balsalobre C, García J and Juárez A
Mol Microbiol, 63 (1), 7-14 (2007)
Structural characterization of the ribosomal P1A-P2B protein dimer by small-angle X-ray scattering and NMR spectroscopy
Grela P, Helgstrand M, Krokowski D, Boguszewska A, Svergun D, Liljas A, Bernadó P, Grankowski N, Akke M and Tchórzewski M
Biochemistry, 46 (7), 1988-1998 (2007)
Highly populated turn conformations in natively unfolded tau protein identified from residual dipolar couplings and molecular simulation
Mukrasch MD, Markwick P, Biernat J, Bergen M, Bernadó P, Griesinger C, Mandelkow E, Zweckstetter M and Blackledge M
J Am Chem Soc, 129 (16), 5235-5243 (2007)
Structural characterization of flexible proteins using small-angle X-ray scattering
Bernadó P, Mylonas E, Petoukhov MV, Blackledge M and Svergun DI
J Am Chem Soc, 129 (17), 5656-5664 (2007)
Protein tyrosine phosphatase oligomerization studied by a combination of 15N NMR relaxation and 129Xe NMR. Effect of buffer containing arginine and glutamic acid
Blobel J, Schmidl S, Vidal D, Nisius L, Bernadó P, Millet O, Brunner E and Pons M
J Am Chem Soc, 129 (18), 5946-5953 (2007)
A novel search engine for virtual screening of very large databases
Vidal D, Thormann M and Pons M
J Chem Inf Model, 46 (2), 836-843 (2006)
Fast 2D NMR ligand screening using Hadamard spectroscopy
Feliz M, García J, Aragón E and Pons M
J Am Chem Soc, 128 (22), 7146-7147 (2006)
New roles for key residues in helices H1 and H2 of the Escherichia coli H-NS N-terminal domain: H-NS dimer stabilization and Hha binding
García J, Madrid C, Juárez A and Pons M
J Mol Biol, 359 (3), 679-689 (2006)
Peptide and amide bond-containing dendrimers
Crespo L, Sanclimens G, Pons M, Giralt E, Royo M and Albericio F
Chem Rev, 105 (5), 1663-1681 (2005)
LINGO, an efficient holographic text based method to calculate biophysical properties and intermolecular similarities
Vidal D, Thormann M and Pons M
J Chem Inf Model, 45 (2), 386-393 (2005)
Interaction between the bacterial nucleoid associated proteins Hha and H-NS involves a conformational change of Hha
García J, Cordeiro TN, Nieto JM, Pons I, Juárez A and Pons M
Biochem J, 388 (Pt 3), 755-762 (2005)
On the origin of the thermostabilization of proteins induced by sodium phosphate
Fayos R, Pons M and Millet O
J Am Chem Soc, 127 (27), 9690-9691 (2005)
Hydrodynamic models and computational methods for NMR relaxation
García de la Torre J, Bernadó P and Pons M
Methods Enzymol, 394, 419-430 (2005)
Macromolecular crowding in biological systems: hydrodynamics and NMR methods
Bernadó P, García de la Torre J and Pons M
J Mol Recognit, 17 (5), 397-407 (2004)
A new class of foldamers based on cis-gamma-amino-L-proline
Farrera-Sinfreu J, Zaccaro L, Vidal D, Salvatella X, Giralt E, Pons M, Albericio F and Royo M
J Am Chem Soc, 126 (19), 6048-6057 (2004)
Interpretation of NMR relaxation properties of Pin1, a two-domain protein, based on Brownian dynamic simulations
Bernadó P, Fernandes MX, Jacobs DM, Fiebig K, García de la Torre J and Pons M
J Biomol NMR, 29 (1), 21-35 (2004)
Evaluation of chiral recognition ability of a novel uranyl-salophen-based receptor: an easy and rapid testing protocol
Dalla Cort A, Murua JI, Pasquini C, Pons M and Schiaffino L
Chemistry, 10 (13), 3301-3307 (2004)
NMR-spectroscopic mapping of an engineered cavity in the I14A mutant of HPr from Staphylococcus carnosus using xenon
Gröger C, Möglich A, Pons M, Koch B, Hengstenberg W, Kalbitzer HR and Brunner E
J Am Chem Soc, 125 (29), 8726-8727 (2003)
Peptide binding induces large scale changes in inter-domain mobility in human Pin1
Jacobs DM, Saxena K, Vogtherr M, Bernado P, Pons M and Fiebig KM
J Biol Chem, 278 (28), 26174-26182 (2003)
Combined use of NMR relaxation measurements and hydrodynamic calculations to study protein association. Evidence for tetramers of low molecular weight protein tyrosine phosphatase in solution
Bernadó P, Akerud T, García de la Torre J, Akke M and Pons M
J Am Chem Soc, 125 (4), 916-923 (2003)
Saturated resins or stress of the resin
Sanclimens G, Crespo L, Pons M, Giralt E, Albericio F and Royo M
Tetrahedron Letters, 44 (9), 1751-1754 (2003)
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