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A Chemical Biology Approach to Understand The Regulation Of Full-Length Phosphoinositide-Dependent Protein Kinase 1 (Pdk1)

Gross, Lissy Zoe Florens; Sacerdoti, MarianaIcon ; Leroux, Alejandro EzequielIcon ; Rinaldi, Jimena JulietaIcon ; Capellari, M. V.; Aramendia, Pedro FranciscoIcon ; Ghode, A.; Anand, G. S.; Klinke, SebastianIcon ; Biondi, Ricardo MiguelIcon
Tipo del evento: Reunión
Nombre del evento: LV Reunión Científica anual SAIB y XIV congreso de PABMB
Fecha del evento: 05/11/2019
Institución Organizadora: Sociedad Argentina de Investigación Bioquímica y Biología Molecular; Pan-American Association For Biochemistry And Molecular Biology;
Título de la revista: Biocell
Editorial: Biocell
ISSN: 0327-9545
Idioma: Inglés
Clasificación temática:
Bioquímica y Biología Molecular

Resumen

Phosphoinositide-dependent protein kinase 1 (PDK1) is a master AGC kinase that phosphorylates at least other 23 AGC kinases, being PKB/Aktthe most relevant substrate downstream of PI3-kinase, important for growth and cell survival and a drug target for cancer treatment. Over the years, our laboratory studied and characterized in detail the catalytic domain of PDK1, as well as the selective activation of substrates such as SGK or S6K, which in order to be phosphorylated require a docking interaction with a hydrophobic site in PDK1 termed the PIF-Pocket. However, this is not the case of Akt/PKB, since it can be activated in a PIF-Pocket independent way. On the other hand, up to date little is known about the mechanistic and structural details of PDK1 full length. Therefore, we are using an interdisciplinary approach to understand how the full length protein is regulated and how this regulation mechanism can be manipulated to specifically inhibit the activation of PKB/Akt. As a result of a medium-scale screening of small compounds we carried out using AlphaScreen technology, we validated a series of small compounds "hits" that modulate PDK1 structure by interaction at different sites on PDK1. We performed hydrogen/deuterium exchange (HDX) experimentsand crystallization screenings to understand the structure of full length PDK1 and how it can be modulated with small compounds. We here present a series of results obtained using HDX on full length PDK1 and the crystal structure of the catalytic domain of PDK1 bound to a small compound identified in our screening. We also present our in vitro studies to understand the oligomerization of PDK1 visualizing single particles using STORM fluorescence microscopy. Finally, we integrate our data to present an updated model on the molecular mechanism of regulation of PDK1.
Palabras clave: Protein Kinase , PDK1 , Structural Biology
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/155081
URL: https://tesorerasaib.wixsite.com/pabmb-saib2019
Colecciones
Eventos(IIBBA)
Eventos de INST.DE INVEST.BIOQUIMICAS DE BS.AS(I)
Eventos(IBIOBA - MPSP)
Eventos de INST. D/INV.EN BIOMED.DE BS AS-CONICET-INST. PARTNER SOCIEDAD MAX PLANCK
Citación
A Chemical Biology Approach to Understand The Regulation Of Full-Length Phosphoinositide-Dependent Protein Kinase 1 (Pdk1); LV Reunión Científica anual SAIB y XIV congreso de PABMB; Salta; Argentina; 2019; 95-95
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