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Towards a Dynamical Understanding of Allostery

Obiettivo

Allostery is a fundamental concept Nature uses to regulate the affinity of a certain substrate to an active site of a protein by binding a ligand to a distant allosteric site. We will design experimental tools to gain an atomistic understanding of the conformational transitions that give rise to allostery. We will approach the problem from two distinctively different directions. First, we will initiate conformational transitions of proteins that per se are not photoswitchable, by cross-linking two sites of an allosteric protein with a photo-switchable azobenzene-moiety to initiate a conformational transition similar to ligand binding. We will use ultrafast infrared spectroscopy to time-resolve the conformational transition. Second, we will experimentally verify a frequently expressed hypothesis that allosteric and active site communicate by exchange of vibrational energy. To that end, we will design a versatile approach that allows us to locally deposit vibrational energy at essentially any site in a protein (e.g. through pumping of an optical chromophore that undergoes ultrafast internal conversion), and to detect its appearance at any other site by using vibrational transitions as local thermometers. Thereby, we will map out a network of connectivity in a given protein. Both approaches will applied both to one and the same protein family. One concrete example are PDZ domains, which are among the smallest allosteric proteins, and for which the connection between allostery and vibrational energy flow has been made explicit, based on computer simulations. We will eventually test this hypothesis experimentally, and provide the foundation for a description of allostery that is on an equal footing as our current understanding of protein folding.

Invito a presentare proposte

ERC-2009-AdG
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Meccanismo di finanziamento

ERC-AG - ERC Advanced Grant

Istituzione ospitante

University of Zurich
Contributo UE
€ 2 400 000,00
Indirizzo
RAMISTRASSE 71
8006 ZURICH
Svizzera

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Tipo di attività
Higher or Secondary Education Establishments
Contatto amministrativo
Peter Hamm (Prof.)
Ricercatore principale
Peter Hamm (Prof.)
Collegamenti
Costo totale
Nessun dato

Beneficiari (1)