{"id":65758,"date":"2018-03-09T22:53:53","date_gmt":"2018-03-09T22:53:53","guid":{"rendered":"https:\/\/www.deberes.net\/tesis\/sin-categoria\/use-of-calix4arenes-to-recover-the-self-assembly-ability-of-mutated-p53-tetramerization-domains\/"},"modified":"2018-03-09T22:53:53","modified_gmt":"2018-03-09T22:53:53","slug":"use-of-calix4arenes-to-recover-the-self-assembly-ability-of-mutated-p53-tetramerization-domains","status":"publish","type":"post","link":"https:\/\/www.deberes.net\/tesis\/quimica-organica\/use-of-calix4arenes-to-recover-the-self-assembly-ability-of-mutated-p53-tetramerization-domains\/","title":{"rendered":"Use of calix[4]arenes to recover the self-assembly ability of mutated p53 tetramerization domains"},"content":{"rendered":"<h2>Tesis doctoral de <strong> Susana Gordo Villoslada <\/strong><\/h2>\n<p>Las interacciones prote\u00edna-prote\u00edna son esenciales en muchos procesos biol\u00f3gicos y por ello resultan dianas terap\u00e9uticas muy prometedoras. Sin embargo, modular artificialmente complejos proteicos resulta todav\u00eda un gran reto. Hasta la fecha, los esfuerzos se han dirigido b\u00e1sicamente hacia la inhibici\u00f3n de interacciones prote\u00edna-prote\u00edna; pocos precedentes describen el dise\u00f1o de mol\u00e9culas que puedan inducir, estabilizar o recuperar el estado oligom\u00e9rico de prote\u00ednas. En relaci\u00f3n a lo \u00faltimo, el sistema formado por el dominio de tetramerizaci\u00f3n de la prote\u00edna p53 (p53td) y sus mutantes oncog\u00e9nicos con oligomerizaci\u00f3n defectuosa representa un excelente modelo para el dise\u00f1o y la evaluaci\u00f3n de mol\u00e9culas que puedan recuperar el estado tetram\u00e9rico nativo. en colaboraci\u00f3n con el prof. Javier de mendoza, se dise\u00f1aron racionalmente compuestos para-guinidinometil-calix[4]arenos capaces de interaccionar con simult\u00e1neamente con las cuatros unidades que estructuran el dominio de tetramerizaci\u00f3n de p53, de tal modo que podr\u00edan estabilizar el estado oligom\u00e9rico de la prote\u00edna. para la evaluaci\u00f3n experimental de dichos ligandos calix[4]arenos, se biosintetizaron tres mutantes naturales de p53td con tetramerizaci\u00f3n defectuosa: g334v, encontrado en c\u00e1nceres de pulm\u00f3n; r337h, asociado al carcinoma adrenocortical infantil; y l344p, asociado al s\u00edndrome l\u00c2\u00a1- fraumeni. tras la s\u00edntesis y purificaci\u00f3n de los compuestos guinidinometil-calix[4]arenos, sus capacidades de interacci\u00f3n con las prote\u00ednas se estudiaron por t\u00e9cnicas biof\u00edsicas, que incluyen resonancia magn\u00e9tica nuclear (sobre la prote\u00edna y sobre el ligando), dicroismo circular, calorimetr\u00eda diferencial de barrido, calorimetr\u00eda isot\u00e9rmica de titulaci\u00f3n, cristalograf\u00eda, espectrometr\u00eda de masas y entrecruzamiento qu\u00edmico. Los resultados muestran claramente que los calix[4]arenos pueden interaccionar con las prote\u00ednas tal y como se hab\u00edan dise\u00f1ado; en consecuencia, estos ligandos son capaces de estabilizar t\u00e9rmica y cin\u00e9ticamente las prote\u00ednas mutantes, recuperando as\u00ed su estado tetram\u00e9rico. Estos resultados son la perfecta prueba del concepto inicialmente planteado: un peque\u00f1o ligando sint\u00e9tico dise\u00f1ado puede estabilizar el estado oligom\u00e9rico de prote\u00ednas estructuralmente defectuosas. El estudio de varios ligandos con diferentes grupos funcionales tambi\u00e9n pone de manifiesto otros fen\u00f3menos de particular relevancia en el campo del reconocimiento de superficies proteicas. Por una parte, el grupo guanidinio tiene un papel clave para la afinidad de la interacci\u00f3n. Por otra parte, la flexibilidad estructural de ambos componentes: la prote\u00edna y el ligando, permite que se establezcan interacciones m\u00e1s estrechas y fuertes, lo que refleja el papel tan ambiguo e impredecible de la entrop\u00eda en procesos de interacci\u00f3n.<\/p>\n<p>&nbsp;<\/p>\n<h3>Datos acad\u00e9micos de la tesis doctoral \u00ab<strong>Use of calix[4]arenes to recover the self-assembly ability of mutated p53 tetramerization domains<\/strong>\u00ab<\/h3>\n<ul>\n<li><strong>T\u00edtulo de la tesis:<\/strong>\u00a0 Use of calix[4]arenes to recover the self-assembly ability of mutated p53 tetramerization domains <\/li>\n<li><strong>Autor:<\/strong>\u00a0 Susana Gordo Villoslada <\/li>\n<li><strong>Universidad:<\/strong>\u00a0 Barcelona<\/li>\n<li><strong>Fecha de lectura de la tesis:<\/strong>\u00a0 30\/06\/2008<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<h3>Direcci\u00f3n y tribunal<\/h3>\n<ul>\n<li><strong>Director de la tesis<\/strong>\n<ul>\n<li>Ernest Giralt Lledo<\/li>\n<\/ul>\n<\/li>\n<li><strong>Tribunal<\/strong>\n<ul>\n<li>Presidente del tribunal: david Andreu mart\u00ednez <\/li>\n<li>Javier De mendoza (vocal)<\/li>\n<li>mauricio Garcia mateu (vocal)<\/li>\n<li>margarita Menendez (vocal)<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Tesis doctoral de Susana Gordo Villoslada Las interacciones prote\u00edna-prote\u00edna son esenciales en muchos procesos biol\u00f3gicos y por ello resultan dianas [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center 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