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  • 1
    Language: English
    In: Chemical reviews, 26 October 2016, Vol.116(20), pp.12785-12820
    Description: Tyrosine-type site-specific recombinases (T-SSRs) have opened new avenues for the predictable modification of genomes as they enable precise genome editing in heterologous hosts. These enzymes are ubiquitous in eubacteria, prevalent in archaea and temperate phages, present in certain yeast strains, but barely found in higher eukaryotes. As tools they find increasing use for the generation and systematic modification of genomes in a plethora of organisms. If applied in host organisms, they enable precise DNA cleavage and ligation without the gain or loss of nucleotides. Criteria directing the choice of the most appropriate T-SSR system for genetic engineering include that, whenever possible, the recombinase should act independent of cofactors and that the target sequences should be long enough to be unique in a given genome. This review is focused on recent advancements in our mechanistic understanding of simple T-SSRs and their application in developmental and synthetic biology, as well as in biomedical research.
    Keywords: DNA Nucleotidyltransferases -- Metabolism ; Integrases -- Metabolism ; Tyrosine -- Metabolism
    ISSN: 00092665
    E-ISSN: 1520-6890
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  • 2
    Language: English
    In: PLoS ONE, 2012, Vol.7(5), p.e36151
    Description: Chemokines are small secreted proteins with important roles in immune responses. They consist of a conserved three-dimensional (3D) structure, so-called IL8-like chemokine fold, which is supported by disulfide bridges characteristic of this protein family. Sequence- and profile-based computational methods have been proficient in discovering novel chemokines by making use of their sequence-conserved cysteine patterns. However, it has been recently shown that some chemokines escaped annotation by these methods due to low sequence similarity to known chemokines and to different arrangement of cysteines in sequence and in 3D. Innovative methods overcoming the limitations of current techniques may allow the discovery of new remote homologs in the still functionally uncharacterized fraction of the human genome. We report a novel computational approach for proteome-wide identification of remote homologs of the chemokine family that uses fold recognition techniques in combination with a scaffold-based automatic mapping of disulfide bonds to define a 3D profile of the chemokine protein family. By applying our methodology to all currently uncharacterized human protein sequences, we have discovered two novel proteins that, without having significant sequence similarity to known chemokines or characteristic cysteine patterns, show strong structural resemblance to known anti-HIV chemokines. Detailed computational analysis and experimental structural investigations based on mass spectrometry and circular dichroism support our structural predictions and highlight several other chemokine-like features. The results obtained support their functional annotation as putative novel chemokines and encourage further experimental characterization. The identification of remote homologs of human chemokines may provide new insights into the molecular mechanisms causing pathologies such as cancer or AIDS, and may contribute to the development of novel treatments. Besides, the genome-wide applicability of our methodology based on 3D protein family profiles may open up new possibilities for improving and accelerating protein function annotation processes.
    Keywords: Research Article ; Biology ; Genetics And Genomics ; Immunology ; Computational Biology ; Biochemistry
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: The Journal of biological chemistry, 22 January 2010, Vol.285(4), pp.2823-33
    Description: The interaction of Abl-Src homology 3 domain (SH3) with the high affinity peptide p41 is the most notable example of the inconsistency existing between the currently accepted description of SH3 complexes and their binding thermodynamic signature. We had previously hypothesized that the presence of interfacial water molecules is partially responsible for this thermodynamic behavior. We present here a thermodynamic, structural, and molecular dynamics simulation study of the interaction of p41 with Abl-SH3 and a set of mutants designed to alter the water-mediated interaction network. Our results provide a detailed description of the dynamic properties of the interfacial water molecules and a molecular interpretation of the thermodynamic effects elicited by the mutations in terms of the modulation of the water-mediated hydrogen bond network. In the light of these results, a new dual binding mechanism is proposed that provides a better description of proline-rich ligand recognition by Abl-SH3 and that has important implications for rational design.
    Keywords: Proto-Oncogene Proteins C-Abl ; Proline -- Chemistry ; Water -- Chemistry ; Src Homology Domains -- Physiology
    ISSN: 00219258
    E-ISSN: 1083-351X
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  • 4
    Language: English
    In: Carbohydrate Research, Nov 15, 2013, Vol.381, p.133(5)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.carres.2013.09.005 Byline: Sergey A. Samsonov, M. Teresa Pisabarro Abstract: Article History: Received 16 July 2013; Revised 6 September 2013; Accepted 7 September 2013
    Keywords: Mucopolysaccharides
    ISSN: 0008-6215
    Source: Cengage Learning, Inc.
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  • 5
    Language: English
    In: BMC Bioinformatics, 01 October 2011, Vol.12(1), p.398
    Description: Abstract Background Protein interactions are essential for coordinating cellular functions. Proteomic studies have already elucidated a huge amount of protein-protein interactions that require detailed functional analysis. Understanding the structural basis of each individual interaction through their structural determination is necessary, yet an unfeasible task. Therefore, computational tools able to predict protein binding regions and recognition modes are required to rationalize putative molecular functions for proteins. With this aim, we previously created SCOWLP, a structural classification of protein binding regions at protein family level, based on the information obtained from high-resolution 3D protein-protein and protein-peptide complexes. Description We present here a new version of SCOWLP that has been enhanced by the inclusion of protein-nucleic acid and protein-saccharide interactions. SCOWLP takes interfacial solvent into account for a detailed characterization of protein interactions. In addition, the binding regions obtained per protein family have been enriched by the inclusion of predicted binding regions, which have been inferred from structurally related proteins across all existing folds. These inferences might become very useful to suggest novel recognition regions and compare structurally similar interfaces from different families. Conclusions The updated SCOWLP has new functionalities that allow both, detection and comparison of protein regions recognizing different types of ligands, which include other proteins, peptides, nucleic acids and saccharides, within a solvated environment. Currently, SCOWLP allows the analysis of predicted protein binding regions based on structure-based inferences across fold space. These predictions may have a unique potential in assisting protein docking, in providing insights into protein interaction networks, and in guiding rational engineering of protein ligands. The newly designed SCOWLP web application has an improved user-friendly interface that facilitates its usage, and is available at http://www.scowlp.org.
    Keywords: Biology
    ISSN: 1471-2105
    E-ISSN: 1471-2105
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  • 6
    Language: English
    In: The journal of physical chemistry. B, 26 June 2008, Vol.112(25), pp.7581-91
    Description: Experimental and theoretical data demonstrate that sequences of heterochiral beta (2,3)-amino acids and a turn-inducing beta-dipeptide adopt hairpin-like structures in methanol. On the basis of extensive canonical and replica exchange MD simulations, we could transfer these findings to water as the solvent of physiological relevance. We show that rationally designed beta-peptides exhibit a higher folding tendency and a more robust hairpin structure formation in water compared with alpha-peptides. Furthermore, our designed scaffold enables the addition of a wide variety of functions without disrupting the structure. Since hairpins are often involved in protein interactions, the very stable hairpin-like fold of our designed beta-peptides might be used as a lead scaffold for the design of molecules that specifically modulate protein-protein interactions. This is demonstrated by application of this concept to the recognition of proline-rich sequences (PRS) by WW domains, an important interaction in cell signaling. We focus on the possibility to imitate the strands 2 and 3 of any WW domain as a minimal motif to recognize their target sequences PPXY. We conclude that rationally designed beta-peptide hairpins can serve as scaffolds not only to tackle PPII recognition but also to open up a way to influence a wide variety of protein-protein interactions.
    Keywords: Peptides -- Chemistry
    ISSN: 1520-6106
    E-ISSN: 15205207
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  • 7
    Language: English
    In: Journal of Computer-Aided Molecular Design, 2011, Vol.25(5), pp.477-489
    Description: Glycosaminoglycans (GAGs) are anionic polysaccharides, which participate in key processes in the extracellular matrix by interactions with protein targets. Due to their charged nature, accurate consideration of electrostatic and water-mediated interactions is indispensable for understanding GAGs binding properties. However, solvent is often overlooked in molecular recognition studies. Here we analyze the abundance of solvent in GAG-protein interfaces and investigate the challenges of adding explicit solvent in GAG-protein docking experiments. We observe PDB GAG-protein interfaces being significantly more hydrated than protein–protein interfaces. Furthermore, by applying molecular dynamics approaches we estimate that about half of GAG-protein interactions are water-mediated. With a dataset of eleven GAG-protein complexes we analyze how solvent inclusion affects Autodock 3, eHiTs, MOE and FlexX docking. We develop an approach to de novo place explicit solvent into the binding site prior to docking, which uses the GRID program to predict positions of waters and to locate possible areas of solvent displacement upon ligand binding. To investigate how solvent placement affects docking performance, we compare these results with those obtained by taking into account information about the solvent position in the crystal structure. In general, we observe that inclusion of solvent improves the results obtained with these methods. Our data show that Autodock 3 performs best, though it experiences difficulties to quantitatively reproduce experimental data on specificity of heparin/heparan sulfate disaccharides binding to IL-8. Our work highlights the current challenges of introducing solvent in protein-GAGs recognition studies, which is crucial for exploiting the full potential of these molecules for rational engineering.
    Keywords: Glycosaminoglycan-protein interfaces ; GRID ; Docking ; Interfacial solvent ; Molecular dynamics ; SCOWLP
    ISSN: 0920-654X
    E-ISSN: 1573-4951
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  • 8
    Language: English
    In: Nucleic acids research, 01 February 2013, Vol.41(4), pp.2394-403
    Description: Site-specific recombinases (SSRs) can perform DNA rearrangements, including deletions, inversions and translocations when their naive target sequences are placed strategically into the genome of an organism. Hence, in order to employ SSRs in heterologous hosts, their target sites have to be introduced into the genome of an organism before the enzyme can be practically employed. Engineered SSRs hold great promise for biotechnology and advanced biomedical applications, as they promise to extend the usefulness of SSRs to allow efficient and specific recombination of pre-existing, natural genomic sequences. However, the generation of enzymes with desired properties remains challenging. Here, we use substrate-linked directed evolution in combination with molecular modeling to rationally engineer an efficient and specific recombinase (sTre) that readily and specifically recombines a sequence present in the HIV-1 genome. We elucidate the role of key residues implicated in the molecular recognition mechanism and we present a rationale for sTre's enhanced specificity. Combining evolutionary and rational approaches should help in accelerating the generation of enzymes with desired properties for use in biotechnology and biomedicine.
    Keywords: Directed Molecular Evolution -- Methods ; Recombinases -- Chemistry
    ISSN: 03051048
    E-ISSN: 1362-4962
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  • 9
    Language: English
    In: Biomacromolecules, 11 August 2014, Vol.15(8), pp.3083-92
    Description: Sulfated glycosaminoglycans (GAGs) can direct cellular processes by interacting with proteins of the extracellular matrix (ECM). In this study we characterize the interaction profiles of chemically sulfated hyaluronan (HA) and chondroitin sulfate (CS) derivatives with bone morphogenetic protein-2 (BMP-2) and investigate their relevance for complex formation with the receptor BMPR-IA. These goals were addressed by surface plasmon resonance (SPR) and ELISA in combination with molecular modeling and dynamics simulation. We found not only the interaction of BMP-2 with GAGs to be dependent on the type and sulfation of GAGs but also BMP-2/GAG/BMPR-IA complex formation. The conformational plasticity of the BMP-2 N-termini plays a key role in the structural and thermodynamic characteristics of the BMP-2/GAG/BMPR-IA system. Hence we propose a model that provides direct insights into the importance of the structural and dynamical properties of the BMP-2/BMPR-IA system for its regulation by sulfated GAGs, in which structural asymmetry plays a key role.
    Keywords: Bone Morphogenetic Protein 2 -- Chemistry ; Bone Morphogenetic Protein Receptors, Type I -- Chemistry ; Glycosaminoglycans -- Chemistry
    ISSN: 15257797
    E-ISSN: 1526-4602
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  • 10
    Language: English
    In: Journal of chemical theory and computation, 11 August 2015, Vol.11(8), pp.3906-18
    Description: Molecular docking is extensively applied to determine the position of a ligand on its receptor despite the rather poor correspondence between docking scores and experimental binding affinities found in several studies, especially for systems structurally unrelated with those used in the scoring functions' training sets. Here, we present a method for the prediction of binding modes and binding free energies, which uses replica exchange molecular dynamics in combination with a receptor-shaped piecewise potential, confining the ligand in the proximity of the receptor surface and limiting the accessible conformational space of interest. We assess our methodology with a set of protein receptor-ligand test cases. In every case studied, the method is able to locate the ligand on the experimentally known receptor binding site, and it gives as output the binding free energy. The added value of our approach with respect to other available methods is that it quickly performs a conformational space search, providing a set of bound (or unbound) configurations, which can be used to determine phenomenological structural and energetic properties of an experimental binding state as a result of contributions provided by diversified multiple binding poses.
    Keywords: Molecular Dynamics Simulation ; Proteins -- Chemistry
    ISSN: 15499618
    E-ISSN: 1549-9626
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