Projektbeschreibung
Mit Kryo-Elektronenmikroskopie die dreidimensionale Struktur von Histon-Deacetylase-Komplexen entschlüsseln
Komplexe mit Histon-Deacetylasen (HDAC) enthalten Histon-modifizierende Enzyme, die Transkriptionsprozesse in Eukaryoten unterdrücken können. Bei gestörter HDAC-Funktion kommt es zu verschiedenen Erkrankungen wie Krebs, entzündlichen Krankheiten und neurologischen Störungen. Noch existieren keine hochauflösenden 3D-Strukturen für HDAC-Komplexe. Das verhindert die Entwicklung von neuartigen Wirkstoffen, die auf spezifische Untereinheiten in Komplexen abzielen, um bestimmte biologische HDAC-Funktionen umzuprogrammieren. Das im Rahmen der Marie-Skłodowska-Curie-Maßnahmen finanzierte Projekt HDACbyCRYOEM wird mithilfe der Kryo-Elektronenmikroskopie (Kryo-EM) die 3D-Strukturen von HDAC-Komplexen der Hefe und des Menschen mit nahezu atomarer Auflösung entschlüsseln. HDAC-Komplexe haben sich im Laufe der Evolution kaum verändert und werden von einer begrenzten Anzahl von Proteinen gebildet, was sie zu einer idealen Zielstruktur für die Einzelpartikel-Kryo-EM macht.
Ziel
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.
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Aufforderung zur Vorschlagseinreichung
Andere Projekte für diesen Aufruf anzeigenFinanzierungsplan
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsKoordinator
3000 Leuven
Belgien