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SUMMARY:Mutate everything: mapping the energetic and allosteric landscapes
  of proteins at scale - Professor Ben Lehner from Wellcome Sanger Institut
 e\, Cambridge  
DTSTART:20240502T130000Z
DTEND:20240502T140000Z
UID:TALK202210@talks.cam.ac.uk
CONTACT:Caroline Newnham
DESCRIPTION:The objective of the new Generative and Synthetic Genomics pro
 gram at the Wellcome Sanger Institute is to produce foundational methods\,
  datasets and models to help transform molecular biology into a predictive
  engineering science.  Towards this goal we have developed methods that co
 mbine mutagenesis with model fitting using machine learning to quantify th
 e effects of millions of sequence variants on the biophysical properties o
 f proteins\, including their fold stabilities\, aggregation and binding af
 finities.  This has allowed us to produce the first comprehensive maps of 
 allosteric communication in proteins.  Thousands of proteins have now been
  genetically-validated as therapeutic targets in hundreds of human disease
 s.  However\, very few have actually been successfully targeted and many a
 re considered ‘undruggable’.  This is particularly true for proteins t
 hat function via protein-protein interactions: direct inhibition of bindin
 g interfaces is difficult\, requiring the identification of allosteric sit
 es. However\, most proteins have no known allosteric sites and a comprehen
 sive allosteric map does not exist for any protein.  We have addressed thi
 s shortcoming by charting multiple global atlases of inhibitory allosteric
  communication in KRAS\, a protein mutated in 1 in 10 human cancers.  We q
 uantified the impact of >26\,000 mutations on the folding of KRAS and its 
 binding to six interaction partners.  Genetic interactions in double mutan
 ts 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 mut
 ations tune the binding specificity of a signalling protein and map the in
 hibitory allosteric sites for an important therapeutic target.  Allosteric
  propagation is particularly effective across the central beta sheet of KR
 AS and multiple surface pockets are genetically-validated as allostericall
 y 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 regulator
 y\, evolutionary and therapeutic potential to tune pathway activation.  Us
 ing the approach described here it should be possible to comprehensively i
 dentify allosteric target sites in many important proteins. 
LOCATION:Biffen Lecture theatre and Zoom
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