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Areas
  • Fundamental biology
  • Ubiquitin
  • Signal transduction
  • Immune signalling
  • Structural biology
  • Protein chemistry
  • Proteases
Diseases
Technologies
Themes / Divisions

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).

Publications

Selected publications from Dr 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

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

Roy MJ, Surudoi M, Kropp A, Hou J, Dai W, Hardy JM, Liang L-Y, Cotton TR, Lechtenberg BC, Dite TA, Ma X, Daly RJ, Patel O, Lucet IS. Structural mapping of the PEAK pseudokinase interactome identifies 14-3-3 as a molecular switch regulating PEAK3/Crk signalling. Acta Crystallographica Section A: Foundations and advances. 2023;79(a2):10.1107/s2053273323086850

Roy MJ, Surudoi MG, Kropp A, Hou J, Dai W, Hardy JM, Liang L-Y, Cotton TR, Lechtenberg BC, Dite TA, Ma X, Daly RJ, Patel O, Lucet IS. Structural mapping of PEAK pseudokinase interactions identifies 14-3-3 as a molecular switch for PEAK3 signaling. Nature Communications. 2023;14(1):10.1038/s41467-023-38869-9

Chen H, Nguyen NH, Magtoto CM, Cobbold SA, Bidgood GM, Guzman LGM, Richardson LW, Corbin J, Au AE, Lechtenberg BC, Feltham R, Sutherland KD, Grohmann C, Nicholson SE, Sleebs BE. Design and characterization of a heterobifunctional degrader of KEAP1. Redox Biology. 2023;59:10.1016/j.redox.2022.102552

Gomez-Soler M, Gehring MP, Lechtenberg BC, Zapata-Mercado E, Ruelos A, Matsumoto MW, Hristova K, Pasquale EB. Ligands with different dimeric configurations potently activate the EphA2 receptor and reveal its potential for biased signaling. iScience. 2022;25(3):10.1016/j.isci.2022.103870

Calleja DJ, Kuchel N, Lu BGC, Birkinshaw RW, Klemm T, Doerflinger M, Cooney JP, Mackiewicz L, Au AE, Yap YQ, Blackmore TR, Katneni K, Crighton E, Newman J, Jarman KE, Call MJ, Lechtenberg BC, Czabotar PE, Pellegrini M, Charman SA, Lowes KN, Mitchell JP, Nachbur U, Lessene G, Komander D. Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro Inhibitors. Frontiers in Chemistry. 2022;10:10.3389/fchem.2022.861209

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):10.1038/s41467-021-27343-z

Light TP, Gomez-Soler M, Wang Z, Karl K, Zapata-Mercado E, Gehring MP, Lechtenberg BC, Pogorelov TV, Hristova K, Pasquale EB. A cancer mutation promotes EphA4 oligomerization and signaling by altering the conformation of the SAM domain. Journal of Biological Chemistry. 2021;297(1):10.1016/j.jbc.2021.100876

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):10.15252/embj.2020106275

Lab research projects

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