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.
United Kingdom, University of Cambridge, PhD, 2012
Germany, University of Lübeck, MSc, 2008
Germany, University of Lübeck, BSc, 2006
University of Melbourne, Honorary Senior Fellow
2016 Fishman Fund Career Development Award, Sanford Burnham Prebys Medical Discovery Institute
2013 Long-term Postdoctoral Fellowship, EMBO
2013 Salje Medal: Best Science PhD, Clare Hall, Cambridge, UK
2023 – 2027, Investigator Grant, NHMRC
2020 – 2023, Ideas Grant (CIA), NHMRC
2020 – 2022, Ideas Grant (CIB), NHMRC
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):168. PMID: 36631489
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):598-615. PMID: 34998453
Lechtenberg BC, Gehring MP, Light TP, Horne CR, Matsumoto MW, Hristova K, Pasquale EB. Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker. Nature Communications. 2021;12(1):7047. PMID: 34857764
Klemm T, Ebert G, Calleja DJ, Allison CC, Richardson LW, Bernardini JP, Lu BG, Kuchel NW, Grohmann C, Shibata Y, Gan ZY, Cooney JP, Doerflinger M, Au AE, Blackmore TR, van der Heden van Noort GJ, Geurink PP, Ovaa H, Newman J, Riboldi-Tunnicliffe A, Czabotar PE, Mitchell JP, Feltham R, Lechtenberg BC, Lowes KN, Dewson G, Pellegrini M, Lessene G, Komander D. Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2. The EMBO Journal. 2020;39(18):e106275. PMID: 32845033
Cotton TR, Lechtenberg BC. Chain reactions: molecular mechanisms of RBR ubiquitin ligases. Biochem Soc Trans. 2020;48(4):1737-50. PMID: 32677670
Shin K*, Lechtenberg BC*, Fujimoto LM, Yao Y, Bartra SS, Plano GV, Marassi FM. Structure of human Vitronectin C-terminal domain and interaction with Yersinia pestis outer membrane protein Ail. Science Advances. 2019;5(9):eaax5068. PMID: 31535027
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):546-50. PMID: 26789245
Lamberto I*, Lechtenberg BC*, Olson EJ*, Mace PD, Dawson PE, Riedl SJ, Pasquale EB. Development and structural analysis of a nanomolar cyclic peptide antagonist for the EphA4 receptor. ACS Chem Biol. 2014;9(12):2787-95. PMID: 25268696
Lechtenberg BC*, Murray-Rust TA*, Johnson DJ, Adams TE, Krishnaswamy S, Camire RM, Huntington JA. Crystal structure of the prothrombinase complex from the venom of Pseudonaja textilis. Blood. 2013;122(16):2777-83. PMID: 23869089
Lechtenberg BC, Johnson DJ, Freund SM, Huntington JA. NMR resonance assignments of thrombin reveal the conformational and dynamic effects of ligation. PNAS. 2010;107(32):14087-92. PMID: 20660315
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.
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.
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.
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.