Martin Renatus, Chemical Biology Therapeutics

Chemical Biology & Therapeutics

Basel, Switzerland

Intrinsic disorder of proteins is a phenomenon that challenged the fundamental understanding of structural biology, which assumed that a defined three dimensional structure is a prerequisite for a defined function. In recent years, it became apparent that intrinsic disorder is a common feature of many key regulatory proteins. Intrinsically disordered proteins (IDPs) are often found at the center of protein interaction networks as they are able to interact with a number of different proteins at high fidelity. Dysregulation of such central hubs may lead to human disease and many IDPs, including several transcription factors such as Myc, are therefore considered promising drug targets. However, identifying potent and specific small molecule modulators for flexible proteins remains a challenge and many modern drug discovery approaches are not able to capture conformational diversity of flexible protein targets.

To successfully discover and develop small molecule drugs for IDPs, a better understanding of such interactions is required. We therefore initiated projects on several disease-relevant transcription factors, with the goal to explore how transcription factors are regulated by their protein binding partners and test concepts to disrupt or stabilize these interactions. In my laboratory, we generate proteins for structural and biophysical studies using well established expression systems, such as insect cells and E.coli. The protein samples are used to verify protein-protein interactions using various biophysical methods, including SPR, BLI, or ITC. Ultimately, we strive to obtain high-resolution structures using X-ray crystallography as well as cryo-electron microscopy. This structural information is a prerequisite for structure-based drug design. In collaboration with project teams consisting of chemists, cell biologists and in vivo pharmacologists, we focus on identifying small molecules that bind to protein or protein complexes and function as inhibitor or activator.

Selected Publications

Azaindoles as Zinc-Binding Small-Molecule Inhibitors of the JAMM Protease CSN5.
Altmann E, Erbel P, Renatus M, Schaefer M, Schlierf A, Druet A, Kieffer L, Sorge M, Pfister K, Hassiepen U, Jones M, Ruedisser S, Ostermeier D, Martoglio B, Jefferson AB, Quancard J.
Angew Chem Int Ed Engl. 2017 Jan 24;56(5):1294-1297.

Targeted inhibition of the COP9 signalosome for treatment of cancer.
Schlierf A, Altmann E, Quancard J, Jefferson AB, Assenberg R, Renatus M, Jones M, Hassiepen U, Schaefer M, Kiffe M, Weiss A, Wiesmann C, Sedrani R, Eder J, Martoglio B.
Nat Commun. 2016 Oct 24;7:13166.

Crystal structure of the human COP9 signalosome.
Lingaraju GM, Bunker RD, Cavadini S, Hess D, Hassiepen U, Renatus M, Fischer ES, Thomä NH.
Nature. 2014 Aug 14;512(7513):161-165.

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