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1.
Nucleic Acids Res ; 43(10): 4785-99, 2015 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-25940631

RESUMEN

Quadruplex nucleic acids can be formed at the ends of eukaryotic chromosomes. Their formation and stabilisation by appropriate small molecules can be used as a means of inhibiting the telomere maintenance functions of telomerase in human cancer cells. The crystal structures have been determined for a number of complexes between these small molecules and human telomeric DNA and RNA quadruplexes. The detailed structural characteristics of these complexes have been surveyed here and the variations in conformation for the TTA and UUA loops have been explored. Loop conformations have been classified in terms of a number of discrete types and their distribution among the crystal structures. Sugar conformation and backbone angles have also been examined and trends highlighted. One particular loop class has been found to be most prevalent. Implications for in particular, rational drug design, are discussed.


Asunto(s)
G-Cuádruplex , Telómero/química , ADN/química , ADN/metabolismo , Humanos , Modelos Moleculares , ARN/química , ARN/metabolismo
2.
Nucleic Acids Res ; 42(Database issue): D358-63, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24234451

RESUMEN

IntAct (freely available at http://www.ebi.ac.uk/intact) is an open-source, open data molecular interaction database populated by data either curated from the literature or from direct data depositions. IntAct has developed a sophisticated web-based curation tool, capable of supporting both IMEx- and MIMIx-level curation. This tool is now utilized by multiple additional curation teams, all of whom annotate data directly into the IntAct database. Members of the IntAct team supply appropriate levels of training, perform quality control on entries and take responsibility for long-term data maintenance. Recently, the MINT and IntAct databases decided to merge their separate efforts to make optimal use of limited developer resources and maximize the curation output. All data manually curated by the MINT curators have been moved into the IntAct database at EMBL-EBI and are merged with the existing IntAct dataset. Both IntAct and MINT are active contributors to the IMEx consortium (http://www.imexconsortium.org).


Asunto(s)
Bases de Datos de Proteínas , Mapeo de Interacción de Proteínas , Internet , Programas Informáticos
3.
Chembiochem ; 15(1): 68-79, 2014 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-24323836

RESUMEN

Heterocyclic diamidines are strong DNA minor-groove binders and have excellent antiparasitic activity. To extend the biological activity of these compounds, a series of arylimidamides (AIAs) analogues, which have better uptake properties in Leishmania and Trypanosoma cruizi than diamidines, was prepared. The binding of the AIAs to DNA was investigated by Tm , fluorescence displacement titration, circular dichroism, DNase I footprinting, biosensor surface plasmon resonance, X-ray crystallography and molecular modeling. These compounds form 1:1 complexes with AT sequences in the DNA minor groove, and the binding strength varies with substituent size, charge and polarity. These substituent-dependent structure and properties provide a SAR that can be used to estimate K values for binding to DNA in this series. The structural results and molecular modeling studies provide an explanation for the differences in binding affinities for AIAs.


Asunto(s)
Amidas/metabolismo , ADN/metabolismo , Amidas/química , Secuencia de Bases , Sitios de Unión , Dicroismo Circular , Cristalografía por Rayos X , ADN/química , Desoxirribonucleasa I/metabolismo , Leishmania/metabolismo , Simulación del Acoplamiento Molecular , Conformación de Ácido Nucleico , Especificidad por Sustrato , Resonancia por Plasmón de Superficie , Temperatura de Transición , Trypanosoma cruzi/metabolismo
4.
Front Genet ; 14: 1251902, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37915827

RESUMEN

Introduction: The normal development of all heart valves requires highly coordinated signaling pathways and downstream mediators. While genomic variants can be responsible for congenital valve disease, environmental factors can also play a role. Later in life valve calcification is a leading cause of aortic valve stenosis, a progressive disease that may lead to heart failure. Current research into the causes of both congenital valve diseases and valve calcification is using a variety of high-throughput methodologies, including transcriptomics, proteomics and genomics. High quality genetic data from biological knowledge bases are essential to facilitate analyses and interpretation of these high-throughput datasets. The Gene Ontology (GO, http://geneontology.org/) is a major bioinformatics resource used to interpret these datasets, as it provides structured, computable knowledge describing the role of gene products across all organisms. The UCL Functional Gene Annotation team focuses on GO annotation of human gene products. Having identified that the GO annotations included in transcriptomic, proteomic and genomic data did not provide sufficient descriptive information about heart valve development, we initiated a focused project to address this issue. Methods: This project prioritized 138 proteins for GO annotation, which led to the curation of 100 peer-reviewed articles and the creation of 400 heart valve development-relevant GO annotations. Results: While the focus of this project was heart valve development, around 600 of the 1000 annotations created described the broader cellular role of these proteins, including those describing aortic valve morphogenesis, BMP signaling and endocardial cushion development. Our functional enrichment analysis of the 28 proteins known to have a role in bicuspid aortic valve disease confirmed that this annotation project has led to an improved interpretation of a heart valve genetic dataset. Discussion: To address the needs of the heart valve research community this project has provided GO annotations to describe the specific roles of key proteins involved in heart valve development. The breadth of GO annotations created by this project will benefit many of those seeking to interpret a wide range of cardiovascular genomic, transcriptomic, proteomic and metabolomic datasets.

5.
Org Biomol Chem ; 9(5): 1328-31, 2011 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-21221451

RESUMEN

Comparative X-ray structure studies reveal that C-F bond incorporation into the peripheral pyrrolidine moieties of the G-quadruplex DNA binding ligand BSU6039 leads to a distinct pyrrolidine ring conformation, relative to the non-fluorinated analogue, and with a different binding mode involving reversal of the pyrrolidinium N(+)-H orientation.


Asunto(s)
Acridinas/química , Flúor/química , G-Cuádruplex , Pirrolidinas/química , Cristalografía por Rayos X , Halogenación , Ligandos
6.
Biochemistry ; 48(8): 1675-80, 2009 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-19173611

RESUMEN

A series of disubstituted acridine ligands have been cocrystallized with a bimolecular DNA G-quadruplex. The ligands have a range of cyclic amino end groups of varying size. The crystal structures show that the diagonal loop in this quadruplex results in a large cavity for these groups, in contrast to the steric constraints imposed by propeller loops in human telomeric quadruplexes. We conclude that the nature of the loop has a significant influence on ligand selectivity for particular quadruplex folds.


Asunto(s)
G-Cuádruplex , Conformación de Ácido Nucleico , Acridinas/química , Cristalografía por Rayos X , Ligandos , Modelos Moleculares , Timina/química
7.
J Am Chem Soc ; 130(21): 6722-4, 2008 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-18457389

RESUMEN

The crystal structure of a complex between the bimolecular human telomeric quadruplex d(TAGGGTTAGGGT)2 and the experimental anticancer drug BRACO-19, has been determined, to 2.5 A resolution. The binding site for the BRACO-19 molecule is at the interface of two parallel-folded quadruplexes, sandwiched between a G-tetrad surface and a TATA tetrad, and held in the site by networks of water molecules. The structure rationalizes the existing structure-activity data and provides a starting-point for the structure-based design of quadruplex-binding ligands


Asunto(s)
Acridinas/química , ADN/química , G-Cuádruplex , Sitios de Unión , Cristalografía por Rayos X , Humanos , Modelos Moleculares , TATA Box , Telómero/química
8.
Circ Genom Precis Med ; 11(2): e001813, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29440116

RESUMEN

BACKGROUND: A systems biology approach to cardiac physiology requires a comprehensive representation of how coordinated processes operate in the heart, as well as the ability to interpret relevant transcriptomic and proteomic experiments. The Gene Ontology (GO) Consortium provides structured, controlled vocabularies of biological terms that can be used to summarize and analyze functional knowledge for gene products. METHODS AND RESULTS: In this study, we created a computational resource to facilitate genetic studies of cardiac physiology by integrating literature curation with attention to an improved and expanded ontological representation of heart processes in the Gene Ontology. As a result, the Gene Ontology now contains terms that comprehensively describe the roles of proteins in cardiac muscle cell action potential, electrical coupling, and the transmission of the electrical impulse from the sinoatrial node to the ventricles. Evaluating the effectiveness of this approach to inform data analysis demonstrated that Gene Ontology annotations, analyzed within an expanded ontological context of heart processes, can help to identify candidate genes associated with arrhythmic disease risk loci. CONCLUSIONS: We determined that a combination of curation and ontology development for heart-specific genes and processes supports the identification and downstream analysis of genes responsible for the spread of the cardiac action potential through the heart. Annotating these genes and processes in a structured format facilitates data analysis and supports effective retrieval of gene-centric information about cardiac defects.


Asunto(s)
Ontología de Genes , Cardiopatías , Proteómica , Biología Computacional , Bases de Datos Genéticas , Corazón , Cardiopatías/genética , Humanos , Anotación de Secuencia Molecular , Fenotipo
9.
Met Ions Life Sci ; 10: 119-34, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22210337

RESUMEN

Metal ions stabilize quadruplex nucleic acids by coordinating the O6 guanine atoms from G-quartets. These quartets form the basic motif of quadruplex structures. This article systematically surveys the available crystallographic data on native quadruplexes, their ligand complexes and (in one instance) a protein complex. Three categories of quadruplex are examined, tetramolecular, bimolecular, and intramolecular: all are formed by telomeric nucleic acid sequences from human or ciliate organisms.


Asunto(s)
G-Cuádruplex , Iones/química , Metales/química , Estructura Molecular , Telómero/química , Telómero/genética
10.
J Med Chem ; 55(1): 209-22, 2012 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-22112241

RESUMEN

The first X-ray crystal structures of nickel(II) and copper(II) salphen metal complexes bound to a quadruplex DNA are presented. Two structures have been determined and show that these salphen-metal complexes bind to human telomeric quadruplexes by end-stacking, with the metal in each case almost in line with the potassium ion channel. Quadruplex and duplex DNA binding is presented for these two and other related salphen complexes, all with side-chains terminating in pyrrolidino end-groups and differing patterns of substitution on the salphen core. The crystal structures are able to provide rationalizations for the structure-activity data, and in particular for the superior quadruplex-binding of the nickel complexes compared to that of the copper-containing ones. The complexes show significant antiproliferative activity for the compounds in a panel of cancer cell lines. They also show telomerase inhibitory activity in the telomerase TRAP-LIG assay.


Asunto(s)
Complejos de Coordinación/química , Cobre , G-Cuádruplex , Modelos Moleculares , Níquel , Fenilendiaminas/química , Telómero/genética , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacología , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Fenilendiaminas/síntesis química , Fenilendiaminas/farmacología , Relación Estructura-Actividad , Telomerasa/antagonistas & inhibidores
11.
Methods ; 43(4): 252-63, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17967696

RESUMEN

DNA quadruplexes are formed from guanine-rich repeats that self-associate into higher order four-stranded structures. These G-rich repeat sequences can be found in both telomeric regions as well as regions proximal to promoters of oncogenes. The compelling evidence that stabilizing these motifs by small molecule ligands can alter cell viability in certain cancer cell lines has led to identification of DNA quadruplex structures as therapeutic targets. Target-based design of selective ligands that target particular quadruplex topologies is heavily reliant on the availability of high-resolution structural information of the intended target. X-ray crystallography can provide this level of detail to atomic resolution. Recently drug discovery programs have refocused on the need for a fuller structural and molecular description of the target molecule. This review describes a crystallographic route to the determination of quadruplex topology, and high-resolution loop structures for target-based ligand design. The review also highlights the methods employed in the design of appropriate DNA sequences and crystallization techniques to solve these unusual DNA structures.


Asunto(s)
Cristalografía por Rayos X/métodos , ADN/química , G-Cuádruplex , Guanina/química , Secuencia de Bases , Cristalización
12.
Bioorg Med Chem Lett ; 16(1): 15-9, 2006 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-16263285

RESUMEN

The crystal structure of the DNA minor groove biphenyl benzimidazole diamidine ligand DB819 has been determined, bound to the DNA sequence d(CGCGAATTCGCG)(2), at a resolution of 1.36 Angstrom. Conditions for reliable in silico docking that reproduce the observed position of the ligand in the minor groove have been determined.


Asunto(s)
Cristalografía por Rayos X/métodos , ADN/química , Imidazoles/química , Bases de Datos de Proteínas , Ligandos , Modelos Químicos , Modelos Moleculares , Conformación de Ácido Nucleico , Unión Proteica , Programas Informáticos
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