GPCRS

Conversion of integral membrane receptors into soluble forms

Coordinatore	UNIVERSITAET ZUERICH    more  Organization address address: Raemistrasse 71 city: ZURICH postcode: 8006 contact info Titolo: Prof. Nome: Andreas Cognome: Plückthun Email: send email Telefono: +1 44 635 5570 Fax: +41 44 635 5712
Nazionalità Coordinatore	Switzerland [CH]
Totale costo	0 €
EC contributo	263˙599 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-IEF-2008
Funding Scheme	MC-IEF
Anno di inizio	2009
Periodo (anno-mese-giorno)	2009-09-01   -   2011-08-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	UNIVERSITAET ZUERICH  Organization address address: Raemistrasse 71 city: ZURICH postcode: 8006 contact info Titolo: Prof. Nome: Andreas Cognome: Plückthun Email: send email Telefono: +1 44 635 5570 Fax: +41 44 635 5712	CH (ZURICH)	coordinator	263˙599.25

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 Obiettivo del progetto (Objective)

'G-protein coupled receptors (GPCRs) are cell surface receptors that mediate the cellular responses to an enormous diversity of endogenous signaling molecules as well as environmental signals. GPCRs are a major target for the pharmaceutical industry as is reflected by the fact that more than 50% of all medicines available today act on a GPCR and represent about a quarter of the top-selling drugs worldwide. However, effective drug design and functional characterization of these receptors is strongly limited by the absence of high-resolution structural information because of the many practical problems of working with membrane proteins. Here, we propose to replace the lipid-exposed hydrophobic residues within the transmembrane domains of GPCRs with more hydrophilic residues to engineer water-soluble variants of GPCRs capable of folding in aqueous solutions. Moreover, detailed comparison of membrane proteins and soluble proteins by protein engineering will also lead to a deeper insight into membrane protein folding and stability with important consequences for the handling of drug targets. Redesigning a GPCR by substituting the hydrophobic amino acids of the protein/lipid interface with suitable polar or charged residues to produce a molecule that is able to fold and function in aqueous solution represents an ambitious protein-engineering problem of high combinatorial complexity. It is improbable that we will reach the desired result in a single step by rational design. Instead, we have chosen a highly interdisciplinary approach that combines the strengths of computational and experimental tools, of design, selection and in vitro evolution. The strategy, we propose to use, relies on the proven expertise of the Plückthun group in the rational design of protein libraries. From these libraries, functional molecules can efficiently be selected by ribosome display methods. Selected sequences can be further optimized using the techniques of directed in vitro evolution.'