Referencia

Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16078-83. Epub 2010 Aug 30

Autores

Marta Nadal, Philippe Mas, Alexandre G. Blanco, Carme Arnan, Maria Solà, Darren J. Hart y Miquel Coll

Resumen

El HCMV replica su DNA en forma de concatámeros, los cuales tienen que ser cortados en genomas simples, y empaquetados dentro de la cápside viral mediante el complejo terminasa. En este artículo, mostramos estudios estructurales y funcionales de la proteína UL89, una subunidad de dicho complejo. La estructura cristalográfica demuestra que la proteína UL89 tiene un plegamiento similar a la RNAsa H/integrasa. También hemos podido comprobar experimentalmente que UL89 posee actividad nucleasa. Por último, señalamos como esta actividad, puede ser inhibida mediante la adición de raltegravir, un inhibidor de la intregasa del HIV recientemente aprobado para el tratamiento del SIDA.

Descripción

During viral replication, herpesviruses package their DNA into the procapsid by means of the terminase protein complex. In human cytomegalovirus (herpesvirus 5), the terminase is composed of subunits UL89 and UL56. UL89 cleaves the long DNA concatemers into unit-length genomes of appropriate length for encapsidation. We used ESPRIT, a high-throughput screening method, to identify a soluble purifiable fragment of UL89 from a library of 18,432 randomly truncated ul89 DNA constructs. The purified protein was crystallized and its three-dimensional structure was solved. This protein corresponds to the key nuclease domain of the terminase and shows an RNase H/integrase-like fold. We demonstrate that UL89-C has the capacity to process the DNA and that this function is dependent on Mn2þ ions, two of which are located at the active site pocket. We also show that the nuclease function can be inactivated by raltegravir, a recently approved anti-AIDS drug that targets the HIV integrase.

Imágen artículo Octubre

REFERENCIA DEL GRUPO E INVESTIGADOR
Nuestra investigación se centra en la estructura tridimensional de las proteínas, los ácidos nucleicos y sus complejos. Utilizamos diversas técnicas de biología molecular y estructural, con especial énfasis en la cristalografía de rayos X. Nuestras principales líneas de investigación son: control de la replicación de ADN, transferencia horizontal de genes, empaquetamiento del ADN en los virus, regulación de la transcripción y maquinaria de replicación viral.

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