Lecture
LIC Lecture: Structure-based development of immunoproteasome inhibitors
- Date
- Monday 24 April 2023
- Time
- Location
-
Lecture Hall
Einsteinweg 57
2333 CC Leiden - Room
- C2
This colloquium on proteasome structure and function relationship will be given by renowned expert scientists Eva Huber and Michael Groll from the Technical University in Munich. They have pioneered the crystal structure of the yeast, mouse and human proteasome that has been of great scientific benefit for the field of design and synthesis of proteasome inhibitors of which at least three molecules have found clinical application to blockbuster dimensions in several types of leukemia.
Abstract
Proteasomes are cytosolic barrel-shaped protease complexes with diverse cellular functions. Several subtypes with different catalytic subunit compositions ensure cell division, cell survival and antigen processing, among them the constitutive proteasome and the immunoproteasome. While proteasome inhibitors that block both variants are in clinical use for the treatment of blood cancer, selective immunoproteasome inhibitors are active as immunosuppressants and currently being investigated in phase II clinical trials. We contributed to this development by determining X-ray structures of mouse constitutive and immunoproteasomes, developing humanized yeast proteasomes and deciphering subtle structural differences that affect inhibitor potency as well as subunit and species selectivity. My talk will present a set of peptidic epoxyketone inhibitors, explain their development and discuss their features in the context of potential applications. In the end, a general overview of structure biology projects covered in the Groll/Huber lab is provided.
