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Towards a Dynamical Understanding of Allostery

Objective

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.

Field of science

  • /natural sciences/chemical sciences/analytical chemistry/spectroscopy
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins

Call for proposal

ERC-2009-AdG
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

UNIVERSITAT ZURICH
Address
Ramistrasse 71
8006 Zürich
Switzerland
Activity type
Other
EU contribution
€ 2 400 000
Principal investigator
Peter Hamm (Prof.)
Administrative Contact
Peter Hamm (Prof.)

Beneficiaries (1)

UNIVERSITAT ZURICH
Switzerland
EU contribution
€ 2 400 000
Address
Ramistrasse 71
8006 Zürich
Activity type
Other
Principal investigator
Peter Hamm (Prof.)
Administrative Contact
Peter Hamm (Prof.)