DRUGE3CRLS

Probing Druggability of Multisubunit Complexes: E3 Cullin RING Ligases

Coordinatore	UNIVERSITY OF DUNDEE    more Spiacenti, non ci sono informazioni su questo coordinatore. Contattare Fabio per maggiori infomrazioni, grazie.
Nazionalità Coordinatore	United Kingdom [UK]
Totale costo	1˙499˙904 €
EC contributo	1˙499˙904 €
Programma	FP7-IDEAS-ERC Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	ERC-2012-StG_20111109
Funding Scheme	ERC-SG
Anno di inizio	2013
Periodo (anno-mese-giorno)	2013-05-01   -   2018-04-30

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	UNIVERSITY OF DUNDEE  Organization address address: Nethergate city: DUNDEE postcode: DD1 4HN contact info Titolo: Dr. Nome: Alessio Cognome: Ciulli Email: send email Telefono: 441382000000 Fax: 441382000000	UK (DUNDEE)	hostInstitution	1˙499˙904.00
2	UNIVERSITY OF DUNDEE  Organization address address: Nethergate city: DUNDEE postcode: DD1 4HN contact info Titolo: Mrs. Nome: Zoe Cognome: Kidd Email: send email Telefono: 441382000000	UK (DUNDEE)	hostInstitution	1˙499˙904.00

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 Obiettivo del progetto (Objective)

'This proposal is centred on the development and application of chemical tools to probe molecular recognition of multiprotein complexes. Although much effort has been devoted to targeting protein-protein interactions using small molecules, these have focused to date on individual gene products or truncated domains, which however do not reflect the physiological organization and activity of many functional proteins. Few successes have been achieved, yet many of the key physical determinants of druggability of surfaces within native protein complexes have remained elusive. The aim of this project is to shed light upon this problem by chemically interrogating biological systems that rely on several subunits working in concert rather than on single proteins working alone. As model system we will investigate the Cullin RING Ligases (CRLs), the largest superfamily of multisubunit E3 ligases in humans. These enzymatic machines are responsible for the recognition, poly-ubiquitination and targeting of substrate proteins to the proteasome for degradation. Many members of this family have crucial roles in cellular physiology and homeostatis, are implicated in a wide range of diseases and are attractive targets for drug discovery. Two interdependent lines of enquiry will be followed. First, we will screen for and elucidate the binding of small molecular fragments and short peptides to identify new druggable surfaces and interfaces on CRLs and their components. Second, we will exploit the nature of the interactions to develop novel chemical probes of CRLs. As the probes are selected and optimised for binding rather than for a particular functional outcome, diverse mechanisms of action are envisaged beyond conventional disruption of the interaction. The successes of this interdisciplinary research will provide a step change in how we interrogate protein-protein interactions of functional and pathological pathways with impact in many areas of chemical biology and drug discovery.'