Opis projektu
Zastosowanie mikroskopii krioelektronowej do rozpuszczania struktury 3D kompleksów deacetylaz histonowych
Kompleksy deacetylaz histonowych (HDAC) zawierają enzymy, które modyfikują histony, wstrzymując procesy transkrypcyjne u eukariotów. Zaburzenia funkcji HDAC skutkują różnymi chorobami, w tym nowotworami, chorobami zapalnymi i zaburzeniami neurologicznymi. Brak wysokorozdzielczych struktur 3D kompleksów HDAC uniemożliwia opracowanie nowych leków, które celują w określone podjednostki kompleksu, aby przeprogramować określone funkcje biologiczne HDAC. Zespół projektu HDACbyCRYOEM finansowanego z działania „Maria Skłodowska-Curie” zamierza wykorzystać mikroskopię krioelektronową (krio-EM) do rozpuszczania trójwymiarowych struktur kompleksów HDAC człowieka i drożdży w rozdzielczości bliskiej atomowej. W procesie ewolucji kompleksy HDAC uległy bardzo niewielkim zmianom. Składają się one z ograniczonej liczby białek, co czyni je idealnym celem dla krio-EM pojedynczych cząstek.
Cel
Histone deacetylase (HDAC) complexes are the main transcriptional repression machineries in eukaryotes. Disruption of their functions can lead to various diseases such as cancers, inflammatory diseases, and neurological disorders. HDAC complexes are composed of multiple subunits that assemble around HDAC enzymes, which have been the most exploited targets for developing small molecule therapeutics.
To expand the diversity of targets and inhibitors available to study HDAC complex biology and fight HDAC-related diseases, the applicant developed phenotypic screens focused on the Sin3 HDAC complex in human and yeast during his PhD training. He also used proteomics approaches to study the global cellular effects of new compounds and predict their targets. However, the absence of high-resolution 3D structures for the Sin3 HDAC complex has hampered the precise understanding and validation of how drugs bind to specific subunits and perturb the overall architecture of the complex to reprogram its biological functions.
Here, we are combining the expertise of the applicant in HDAC complex biology and druggability, to that of his host laboratory in cryo-electron microscopy (cryo-EM) to solve the 3D structures of the human and yeast Sin3 HDAC complex at near atomic resolution. This complex is highly conserved between species and is formed by a dozen proteins, making it an ideal candidate for single-particle cryo-EM. The applicant has already acquired promising preliminary data, including partial purifications of both human and yeast Sin3 HDAC complexes. The pioneer structures that will emerge from this work will have a high impact in the fields of transcriptomics and epigenetics since they will improve our understanding of HDAC complex arrangements, while helping validating long-standing hypotheses on transcriptional repression mechanisms. The proposed 3D models will also serve as starting points for further systematic structure-based design of new HDAC complex inhibitors.
Dziedzina nauki
Słowa kluczowe
Program(-y)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Zaproszenie do składania wniosków
Zobacz inne projekty w ramach tego zaproszeniaSystem finansowania
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsKoordynator
3000 Leuven
Belgia