Tilman Flock is awarded the Max Perutz Student Prize 2015

Big congratulations to Tilman to win this year’s Max Perutz Student Prize.

The Max Perutz Student Prize is awarded annually for outstanding work performed at the LMB prior to the award of a PhD. The 2015 prize has been awarded to Tilman Flock, for his comprehensive computational analysis of GTP-binding proteins (G proteins), revealing the universal nature of their interactions and activation.

Tilman, a third year PhD student in the group of Madan Babu in the Structural Studies Division, undertook a systematic analysis of over 80 structures and 950 sequences of G proteins from different species to reveal how the core mechanism of activation and recognition is conserved, even while new specific interactions evolve. In humans there are over 800 G protein-coupled receptors which, upon binding of an extracellular ligand, activate one or more of 16 different G proteins by triggering the exchange of GDP for GTP, thus initiating a series of signalling pathways. It is these receptors that allow us to smell different chemicals, respond to adrenalin, and sense neurotransmitters in the brain, amongst many other functions. More than 30% of all prescribed small molecule drugs act by stimulating or inhibiting them. Since the 1980’s, there have been over 11,000 publications relating to how G proteins work. Tilman’s elegant methodological approach unifies a vast amount of data, providing a framework for the whole field. It is a general approach that can be extended to other proteins, and it shows the power of large-scale analysis of the ever-growing mass of published data.

See Flock et al, Nature 524, 173-179 (2015).

The research student prize is awarded by the Max Perutz Fund. The Fund was established for the promotion and advancement of education and research in molecular biology and allied biomedical sciences.

Photo and text are taken from the LMB website.

Probing Gαi1 protein activation at single-amino acid resolution

We present comprehensive maps at single-amino acid resolution of the residues stabilizing the human Gαi1 subunit in nucleotide- and receptor-bound states. We generated these maps by measuring the effects of alanine mutations on the stability of Gαi1 and the rhodopsin-Gαi1 complex. We identified stabilization clusters in the GTPase and helical domains responsible for structural integrity and the conformational changes associated with activation. In activation cluster I, helices α1 and α5 pack against strands β1-β3 to stabilize the nucleotide-bound states. In the receptor-bound state, these interactions are replaced by interactions between α5 and strands β4-β6. Key residues in this cluster are Y320, which is crucial for the stabilization of the receptor-bound state, and F336, which stabilizes nucleotide-bound states. Destabilization of helix α1, caused by rearrangement of this activation cluster, leads to the weakening of the interdomain interface and release of GDP. The paper by Dawei Sun, Tilman Flock et al can be viewed here.