A/Prof Bernhard Lechtenberg, Lab Head | WEHI Researcher Profile

Q: Catalytic mechanism and regulation of RBR E3 ubiquitin ligases

RBR E3 ubiquitin ligases are highly regulated enzymes that are generally found in an autoinhibited conformation and are only activated upon specific upstream signals. They use a distinct 2-step catalytic mechanism and contain an active site in their RING2 domain. In the last few years, we have made vast progress on unravelling the general catalytic mechanism and regulation of the RBR E3 ubiquitin ligase family, e.g., Lechtenberg et al., 2016, Nature; Cotton et al. Molecular Cell 2022, Wang & Cotton et al, Nature Communications 2023. How are RBR E3 ligases retained in their autoinhibited conformation? How are they activated and what conformational changes are necessary? What residues and features are critical for their E3 ligase activity?

Q: Structure and function of RBR E3 ubiquitin ligase complexes

Some of the RBR E3 ubiquitin ligases are part of larger complexes.For example, the ligase HOIP is part of the linear ubiquitin chain assembly complex (LUBAC). LUBAC is a regulator of innate immunity and cell death downstream of the TNF receptor and has been linked to autoimmune diseases and inflammation.We study the composition of these complexes and how they affect E3 ligase activity. We aim to solve the structure of these complexes using X-ray crystallography and cryo-electron microscopy, which will provide functional insights and guide development of small molecules that target these E3 ligase complexes.

Q: RBR E3 ubiquitin ligase signalling networks

Many of the 14 members of the RBR family in humans have not been well studied, and we do not appreciate their important cellular functions.We use mass spectrometry and cell biology in conjunction with biochemistry and structural biology to unravel the signalling networks of these enzymes.Our goal is to develop annotated interaction networks of specific RBR E3 ligases and identify their substrates, cofactors, and upstream regulators. This will provide comprehensive novel insights into their biological and pathophysiological roles.We further aim to develop probes and inhibitors for specific E3 ligases as research tools and leads for drug development.

Q: E3 ubiquitin ligases in drug discovery

E3 ubiquitin ligases are often highly specific enzymes that regulate fundamental cellular functions and thus are involved in many human diseases such as inflammation, cancers, and neurodegenerative diseases including Parkinson’s disease. E3 ligases therefore constitute novel therapeutic targets in treating these diseases.In addition, certain E3 ligases induce the degradation of specific proteins. This activity can be hijacked and directed towards other, disease-causing proteins using bivalent small molecule drugs known as targeted protein degrader drugs.Together with other researchers at WEHI and in Australia, including medicinal chemists, biologists, and clinicians, we aim to develop small molecule probes and drug candidates that bind E3 ligases. These small molecules may be used as direct E3 ligase inhibitors, or as E3 ligase recruiters in targeted protein degrader drugs.

About

Throughout my career I have used structural biology and biochemistry to understand the molecular basis of diseases caused by misbehaving enzymes in the human body. My rationale is that a thorough understanding on the molecular level of the disease-causing enzymes and their effects on cellular signalling pathways is essential for successful target identification and drug discovery.

I am particularly interested in the action of the E3 ubiquitin ligases, a vast and diverse family of more than 700 proteins in the human body. E3 ligases catalyse ubiquitination, one of the most diverse post-translational modifications that regulates nearly all processes inside a human cell.

In my lab, we utilise different techniques such as X-ray crystallography, cryo-EM, biochemistry, biophysics, cell biology and proteomics to comprehensively characterise E3 ligases from the molecular to the cellular level and enable E3 ligases in small molecule drug discovery via inhibitors and targeted protein degradation (PROTACs).

Education

Joint appointments

Grants and funding

Publications

Selected publications from A/Prof Bernhard Lechtenberg

Wang XS, Cotton TR, Trevelyan SJ, Richardson LW, Lee WT, Silke J, Lechtenberg BC. The unifying catalytic mechanism of the RING-between-RING E3 ubiquitin ligase family. Nature Communications. 2023;14(1):10.1038/s41467-023-35871-z

Cotton TR, Cobbold SA, Bernardini JP, Richardson LW, Wang XS, Lechtenberg BC. Structural basis of K63-ubiquitin chain formation by the Gordon-Holmes syndrome RBR E3 ubiquitin ligase RNF216. Molecular Cell. 2022;82(3):10.1016/j.molcel.2021.12.005

Lechtenberg BC, Rajput A, Sanishvili R, Dobaczewska MK, Ware CF, Mace PD, Riedl SJ. Structure of a HOIP/E2~ubiquitin complex reveals RBR E3 ligase mechanism and regulation. Nature. 2016;529(7587):10.1038/nature16511

Jochem M, Cobbold SA, Goodman CA, Kueng C, Cerra A, Fielden LF, Kim ML, Schenk P, Agarwal R, Wang XS, Scutts SR, Pandos M, Tang L, Hermanns T, Devine SM, Brzozowski M, Shibata Y, Geoghegan ND, McLean CA, Lechtenberg BC, Hofmann K, Gregorevic P, Komander D. Ubiquitination of glycogen and metabolites in cells and tissues. Nature. 2026;:10.1038/s41586-026-10548-x

Chua NK, González-Robles TJ, Reddington CJ, Dudley-Fraser J, Birkinshaw RW, Han J, Solano A, Wong SW, Kochańczyk T, Peter JJ, Nakasone MA, Aust F, Munro J, Tong YH, Iskander J, Abeysekera W, Garnham A, Huckstep H, Ritchie ME, Wertz I, Hymowitz S, Kumar S, Conaway RC, Privé GG, Bullock AN, Babon JJ, Klevit RE, Lorenz S, Ciulli A, Fischer ES, Thomä NH, Nowak RP, Schulman BA, Rapé M, Rittinger K, Pagan JK, Bahlo M, Mackay JP, Mace PD, Lima CD, Hay RT, Komander D, Lechtenberg BC, Joazeiro CAP, Pagano M, Hofmann K, Feltham R. The E3-ome gene-centric compendium reveals the human E3 ligase landscape. Cell. 2026;189(7):10.1016/j.cell.2026.01.029

Wang XS, Jiou J, Cerra A, Cobbold SA, Jochem M, Mak KHT, Corcilius L, Silke J, Payne RJ, Goddard-Borger ED, Komander D, Lechtenberg BC. The RBR E3 ubiquitin ligase HOIL-1 can ubiquitinate diverse non-protein substrates in vitro. Life Science Alliance. 2025;8(6):10.26508/lsa.202503243

M. Bader S, Calleja DJ, Devine SM, Kuchel NW, Lu BGC, Wu X, Birkinshaw RW, Bhandari R, Loi K, Volpe R, Khakham Y, Au AE, Blackmore TR, Mackiewicz L, Dayton M, Schaefer J, Scherer L, Stock AT, Cooney JP, Schoffer K, Maluenda A, Kleeman EA, Davidson KC, Allison CC, Ebert G, Chen G, Katneni K, Klemm TA, Nachbur U, Georgy SR, Czabotar PE, Hannan AJ, Putoczki TL, Tanzer M, Pellegrini M, Lechtenberg BC, Charman SA, Call MJ, Mitchell JP, Lowes KN, Lessene G, Doerflinger M, Komander D. A novel PLpro inhibitor improves outcomes in a pre-clinical model of long COVID. Nature Communications. 2025;16(1):10.1038/s41467-025-57905-4

Matsumoto M, Gomez-Soler M, Lombardi S, Lechtenberg BC, Pasquale EB. Missense mutations of the ephrin receptor EPHA1 associated with Alzheimer’s disease disrupt receptor signaling functions. Journal of Biological Chemistry. 2025;301(2):10.1016/j.jbc.2024.108099

Lechtenberg BC, Komander D. Just how big is the ubiquitin system?. Nature Structural & Molecular Biology. 2024;31(2):10.1038/s41594-023-01208-z

Gomez-Soler M, Olson EJ, de la Torre ER, Zhao C, Lamberto I, Flood DT, Danho W, Lechtenberg BC, Riedl SJ, Dawson PE, Pasquale EB. Lipidation and PEGylation strategies to prolong the in vivo half-life of a nanomolar EphA4 receptor antagonist. European Journal of Medicinal Chemistry. 2023;262:10.1016/j.ejmech.2023.115876