Dear All,

It is my great pleasure to invite you, on behalf of dr Adam Kłosin, to the next Nencki Institute Seminar which will take place on Thursday August 31^st at 3pm in the CN lecture Hall. We will host Prof. Ben Lehner, Coordinator of the Systems and Synthetic Biology Department at the Centre for Genomic Regulation (CRG) in Barcelona, and a Senior Group Leader at the Wellcome Sanger Institute in Cambridge, UK.

Ben’s Laboratory has been developing the use of large DNA libraries to precisely quantify the effects of millions of mutant variants on protein functions. They have successfully applied this revolutionary approach to chart the genetic landscapes of protein folding (Faure et al., Nature 2022), amyloid aggregation (Seuma et al., eLife 2021), splicing (Baeza-Centurion et al., Cell 2019), and tRNA stability (Domingo at al., Nature 2018).  The long-termgoal of his team is to produce models that allow researchers to understand and engineer proteins so that they can produce the next wave of therapeutics and drive forward bioengineering.

Ben’s long list of achievements and honors includes three ERC Grants, The FABS Anniversary Prize (2010), The National Research Prize of Catalonia (2012), The Genetics Society Balfour Prize (2015), EMBO Gold Medal (2016), Liliane Bettencourt Prize for Life Sciences (2016). He is also a Member of the European Molecular Biology Organisation (since 2017) and a Fellow of the Royal Society (since 2023).

Prof. Ben Lehner will give a lecture entitled: Mutate everything: the energetic and allosteric landscape of KRAS.

Abstract

Thousands of proteins have now been genetically-validated as therapeutic targets in hundreds of human diseases.  However, very few have actually been successfully targeted and many are considered ‘undruggable’.  This is particularly true for proteins that function via protein-protein interactions: direct inhibition of binding interfaces is difficult, requiring the identification of allosteric sites. However, most proteins have no known allosteric sites and a comprehensive allosteric map does not exist for any protein.  Here we address this shortcoming by charting multiple global atlases of inhibitory allosteric communication in KRAS, a protein mutated in 1 in 10 human cancers.  We quantified the impact of >26,000 mutations on the folding of KRAS and its binding to six interaction partners.  Genetic interactions in double mutants allowed us to perform biophysical measurements at scale, inferring >22,000 causal free energy changes, a similar number of measurements as the total made for proteins to date. These energy landscapes quantify how mutations tune the binding specificity of a signalling protein and map the inhibitory allosteric sites for an important therapeutic target.  Allosteric propagation is particularly effective across the central beta sheet of KRAS and multiple surface pockets are genetically-validated as allosterically active, including a distal pocket in the C-terminal lobe of the protein.  Allosteric mutations typically inhibit binding to all tested effectors but they can also change the binding specificity, revealing the regulatory, evolutionary and therapeutic potential to tune pathway activation.  Using the approach described here it should be possible to rapidly and comprehensively identify allosteric target sites in many important proteins.

The seminar will be followed by a get together.

With best wishes
Aleksandra Pękowska