The Shaw Prize in Life Science and Medicine 2023 is awarded in equal shares to Patrick Cramer, Director, Department of Molecular Biology, Max Planck Institute for Multidisciplinary Sciences and President-Elect of the Max Planck Society, Germany and Eva Nogales, Distinguished Professor of Biochemistry, Biophysics and Structural Biology, Department of Molecular and Cell Biology, University of California, Berkeley, USA for pioneering structural biology that enabled visualisation, at the level of individual atoms, of the protein machines responsible for gene transcription, one of life’s fundamental processes. They revealed the mechanism underlying each step in gene transcription, how proper gene transcription promotes health, and how dysregulation causes disease.
The Central Dogma, a theory put forward in 1958 by Francis Crick, is the fundamental concept of life. Three crucial molecules are involved: DNA houses an organism’s genetic blueprint. The DNA genome contains the information required to produce all of an organism’s proteins. Proteins endow cells, tissues, and organisms with their forms and capabilities. Messenger RNA (mRNA) is the intermediate molecule that links DNA to proteins. Particular DNA instructions are converted into individual mRNA molecules to produce specific proteins by a process called gene transcription. Crucially, transcription of specific genes must occur at the correct times and in the correct cellular locations so that the subsets of proteins required for function are only produced when and where they are needed. The gene transcription process has four steps: 1. Initiation; 2. Pausing/ Promoter Clearance; 3. Elongation; 4. Termination. This year’s Shaw Prize recipients, Eva Nogales and Patrick Cramer, pioneered structural biology approaches to enable visualisation, at the level of the individual atoms, of the protein machines responsible for gene transcription. They revealed the molecular mechanism underlying each step in gene transcription, and the importance of proper gene transcription to promote health and prevent disease.
Visualising biology at the atomic level requires determining the structures of the tiny but highly complicated machines that catalyse life processes. Two major approaches are used: x-ray crystallography and cryo-electron microscopy. Eva Nogales pioneered cryo-electron microscopy to transform our understanding of the earliest steps in gene transcription by focusing her efforts on the transcription pre-initiation complex (PIC). The core of this mini-machine is composed of 14 proteins and DNA and it is required for the launch of the gene transcription process. What is remarkable is that the PIC complex is scarce, fragile, and extremely flexible, all of which made the structures Nogales captured a Herculean accomplishment. Nogales revealed how the main player in the complex, a protein called RNA Polymerase II, engages DNA, how the DNA double helix is opened up to expose the site needed for the PIC complex to bind, how, once bound, the PIC complex is stabilised on the DNA, and how coupling occurs between PIC states to allow transcription initiation. Patrick Cramer used x-ray crystallography and cryo-electron microscopy to determine many breathtaking structures capturing the sequential steps of gene transcription. Cramer’s array of structures includes the full PIC, a 46 protein machine that contains crucial players called Mediator and TFIIH. Cramer also solved structures of RNA polymerase II after it initiates synthesis of an mRNA messenger. These structures include the paused elongation complex, the elongation complex in action, the elongation complex together with the nucleosome (nucleosomes are proteins with DNA wrapped around them and the elongation complex must clear them to proceed), the elongation complex with the nucleosome and remodeling factors, and the elongation complex with the pre-mRNA splicing complex (the splicing complex stitches mRNAs together following elongation). Combined, Cramer’s extraordinary structures provide the world’s first “movie” of gene transcription.
Nogales’ and Cramer’s landmark discoveries drove a paradigm shift in our understanding of one of life’s most central processes: gene transcription. They showed how transcription can initiate and proceed, and how transcription is regulated to enable cells to differentiate so that organisms can properly develop and function.
Life Science and Medicine Selection Committee
The Shaw Prize
30 May 2023 Hong Kong