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Peer-reviewedCC BY 4.0Acta Crystallographica Section D: Structural Biology

Fragment-based active-site exploration of urethane hydrolases reveals a diversity of urethane binding modes

  • Deniz Bicer1,2
  • Diana Kochubei3
  • Rosie Graham1,4
  • Samuel Peña-Díaz1,4
  • Laura Rotilio1,5
  • Nikolaj L. Villadsen1,6
  • Andreas Sommerfeldt1,6
  • Martin B. Johansen6
  • Alexander Sandahl1,6
  • Søren S. Thirup1,2
  • J. Preben Morth1,5
  • Daniel E. Otzen1,4
6 affiliations
  1. 1EnZync Center for Enzymatic Deconstruction of Thermoset Plastics, Denmark
  2. 2Department of Molecular Biology and Genetics Aarhus University Universitetsbyen 81 8000 Aarhus Denmark
  3. 3School of Science Constructor University Campus Ring 1 28759 Bremen Germany
  4. 4Interdisciplinary Nanoscience Center (iNANO) Aarhus University Gustav Wieds Vej 14 8000 Aarhus Denmark
  5. 5Biotechnology and Biomedicine Technical University of Denmark Søltofts Plads 2800 Kongens Lyngby Denmark
  6. 6Danish Technological Institute Kongsvang Alle 29 8000 Aarhus Denmark
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Abstract

Recent advances in the discovery, characterization and engineering of urethanases provide new opportunities for the sustainable biocatalytic degradation of polyurethane waste. A mechanistic understanding of enzyme–plastic inter­actions is essential for structure-based engineering to enhance urethanase activity. However, the extremely complex and hydrophobic nature of polyurethane makes it challenging to elucidate the structural basis of enzyme–plastic interactions. Here, we used a fragment-based approach to characterize the active sites of two novel urethanases called amidase U11 and esterase AXPUR5 with different catalytic scaffolds, employing a crystallographic fragment-screening campaign to map subpockets in the active site and validate these subpockets as plastic binding sites by using soluble plastic fragment analogues that mimic the substrate, transition state or product. We resolved 42 high-resolution structures for both esterase AXPUR5 and amidase U11. The fragment-based approach identified new substrate-binding subpockets, while interactions of plastic mimetics in the active site provided a mechanistic understanding of the recognition and binding of polyurethane fragments by these subpockets. These results highlight a diversity of binding modes among urethanases towards different polyurethane fragments.

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Cite

BibTeXRIS
BibTeX
@article{bicer2026fragmentbased,
  title = {{Fragment-based active-site exploration of urethane hydrolases reveals a diversity of urethane binding modes}},
  author = {Deniz Bicer and Diana Kochubei and Rosie Graham and Samuel Peña-Díaz and Laura Rotilio and Nikolaj L. Villadsen and Andreas Sommerfeldt and Martin B. Johansen and Alexander Sandahl and Søren S. Thirup and J. Preben Morth and Daniel E. Otzen},
  journal = {Acta Crystallographica Section D: Structural Biology},
  year = {2026},
  month = oct,
  doi = {10.1107/s2059798326010624},
  url = {https://doi.org/10.1107/s2059798326010624},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Fragment-based active-site exploration of urethane hydrolases reveals a diversity of urethane binding modes
AU  - Deniz Bicer
AU  - Diana Kochubei
AU  - Rosie Graham
AU  - Samuel Peña-Díaz
AU  - Laura Rotilio
AU  - Nikolaj L. Villadsen
AU  - Andreas Sommerfeldt
AU  - Martin B. Johansen
AU  - Alexander Sandahl
AU  - Søren S. Thirup
AU  - J. Preben Morth
AU  - Daniel E. Otzen
PY  - 2026
DA  - 2026/10/26
JO  - Acta Crystallographica Section D: Structural Biology
DO  - 10.1107/s2059798326010624
UR  - https://doi.org/10.1107/s2059798326010624
AB  - Recent advances in the discovery, characterization and engineering of urethanases provide new opportunities for the sustainable biocatalytic degradation of polyurethane waste. A mechanistic understanding of enzyme–plastic inter­actions is essential for structure-based engineering to enhance urethanase activity. However, the extremely complex and hydrophobic nature of polyurethane makes it challenging to elucidate the structural basis of enzyme–plastic interactions. Here, we used a fragment-based approach to characterize the active sites of two novel urethanases called amidase U11 and esterase AXPUR5 with different catalytic scaffolds, employing a crystallographic fragment-screening campaign to map subpockets in the active site and validate these subpockets as plastic binding sites by using soluble plastic fragment analogues that mimic the substrate, transition state or product. We resolved 42 high-resolution structures for both esterase AXPUR5 and amidase U11. The fragment-based approach identified new substrate-binding subpockets, while interactions of plastic mimetics in the active site provided a mechanistic understanding of the recognition and binding of polyurethane fragments by these subpockets. These results highlight a diversity of binding modes among urethanases towards different polyurethane fragments.
SN  - 2059-7983
ER  -