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SUMMARY:LMB Seminar: The allosteric landscape of a protein - Ben Lehner FR
 S FMedSci\, Head of Generative and Synthetic Genomics\, Wellcome Sanger In
 stitute\, Cambridge\, UK\, ICREA Professor\, Systems and Synthetic Biology
 \, CRG\, Barcelona\, ES
DTSTART:20240129T110000Z
DTEND:20240129T120000Z
UID:TALK202675@talks.cam.ac.uk
CONTACT:Scientific Meetings Co-ordinator
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 
 are considered ‘undruggable’.  This is particularly true for proteins
  that function via protein-protein interactions: direct inhibition of bind
 ing interfaces is difficult\, requiring the identification of allosteric s
 ites. However\, most proteins have no known allosteric sites and a compreh
 ensive allosteric map does not exist for any protein.  We have addressed 
 this shortcoming by charting multiple global atlases of inhibitory alloste
 ric 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\, inferrin
 g >22\,000 causal free energy changes\, a similar number of measurements a
 s the total made for proteins to date. These energy landscapes quantify ho
 w mutations tune the binding specificity of a signalling protein and map t
 he inhibitory allosteric sites for an important therapeutic target.  Allo
 steric propagation is particularly effective across the central beta sheet
  of KRAS and multiple surface pockets are genetically-validated as alloste
 rically active\, including a distal pocket in the C-terminal lobe of the p
 rotein.  Allosteric mutations typically inhibit binding to all tested eff
 ectors but they can also change the binding specificity\, revealing the re
 gulatory\, evolutionary and therapeutic potential to tune pathway activati
 on.  Using the approach described here it should be possible to comprehen
 sively identify allosteric target sites in many important proteins. \n\nRe
 ferences\n1.	Weng C\, Faure AJ\, Escobedo A\, Lehner B. The energetic and 
 allosteric landscape for KRAS inhibition. Nature. 2023 Dec 18. \n2.	Faure 
 AJ*\, Domingo J*\, Schmiedel JM*\, Hidalgo-Carcedo C\, Diss G\, Lehner B. 
 Mapping the energetic and allosteric landscapes of protein binding domains
 . Nature. 2022 Apr\;604(7904):175-183.\n3.	Seuma M\, Lehner B*\, Bolognesi
  B*. An atlas of amyloid aggregation: the impact of substitutions\, insert
 ions\, deletions and truncations on amyloid beta fibril nucleation. Nature
  Communications. 2022 Nov 18\;13(1):7084.\n4.	Schmiedel J\, Lehner B. Dete
 rmining protein structures using deep mutagenesis.  Nature Genetics. 2019 
 Jul 51(7):1177-1186.  \n5.	Baeza-Centurion P\, Miñana B\, Schmiedel JM\, 
 Valcárcel J*\, Lehner B*. Combinatorial genetics reveals a scaling law fo
 r the effects of mutations on splicing. Cell. 2019 24\;176(3):549-563.\n6.
 	Domingo J\, Diss G\, Lehner B. Pairwise and higher-order genetic interact
 ions during the evolution of a tRNA. Nature. 2018 Jun\;558(7708):117-121.\
 n7.	Faure A\, Martí-Aranda A\, Hidalgo-Carcedo C\, Schmiedel JM\, Lehner 
 B.  The genetic architecture of protein stability. BioRxiv 2023.10.27.5643
 39\; doi: https://doi.org/10.1101/2023.10.27.564339\n8.	Topolska N\, Beltr
 an A\, Lehner B. Deep indel mutagenesis reveals the impact of insertions a
 nd deletions on protein stability and function. BioRxiv 2023.10.06.561180\
 ; doi: https://doi.org/10.1101/2023.10.06.561180\n9.	Toledano I\, Supek F\
 , Lehner B. Genome-scale quantification and prediction of pathogenic stop 
 codon readthrough by small molecules.  BioRxiv 2023.08.07.552350\; doi: ht
 tps://doi.org/10.1101/2023.08.07.552350\n\nTwitter/X Handle - @BenLehner
LOCATION:In person in the Max Perutz Lecture Theatre (CB2 0QH) and via Zoo
 m\, link: https://mrc-lmb-cam-ac-uk.zoom.us/j/96896374524?pwd=VFJYbkZmRlZQ
 REJ6a1QwelRSdEZwdz09
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