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Discovery of a non-canonical prototype long-chain monoacylglycerol lipase through a structure-based endogenous reaction intermediate complex
Open accessPreprint — published as 10.1038/s41467-023-43354-4 · Paper page
Abstract
The identification and characterization of enzyme function is largely lacking behind the rapidly increasing availability of large numbers of sequences and associated high-resolution structures. This is often hampered by lack of knowledge on in vivo relevant substrates. Here, we present a case study of a high-resolution structure of an unusual orphan lipase in complex with an endogenous C18 monoacylglycerol ester reaction intermediate from the expression host, which is insoluble under aqueous conditions and thus not accessible for studies in solution. The data allowed its functional characterization as a prototypic long-chain monoacylglycerol lipase, which uses a minimal lid domain to position the substrate through a hydrophobic tunnel directly to the enzyme’s active site. Knowledge about the molecular details of the substrate binding site allowed us to modulate the enzymatic activity by adjusting protein/substrate interactions, demonstrating the potential of our findings for future biotechnology applications.
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Highly accurate protein structure prediction with AlphaFold
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Metadata
- Authors
- Pinotsis, N., Krüger, A., Tomas, N., Chatziefthymiou, S. D., Litz, C., Mortensen, S. A., Daffé, M., Marrakchi, H., Antranikian, G., & Wilmanns, M.
- Affiliations
- National and Kapodistrian University of Athens (GR)
- Hamburg University of Technology (DE)
- Centre National de la Recherche Scientifique (FR)
- European Molecular Biology Laboratory (DE)
- Universität Hamburg (DE)
- Corresponding author
- Wilmanns, Matthias
- ORCID
- Venue
- Nature Communications
- Publisher
- openRxiv
- Published
- 2022-04-07
- Volume
- 14
- Issue
- 1
- Pages
- 7649-7649
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC10682391
- OpenAlex
- W4389049710
- Cited by
- 14
- References
- 1
- Citations by year
- 2026: 8 · 2025: 3 · 2024: 3
- FWCI
- 1.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion, cc-by)
- HAL (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- tub.dok (Hamburg University of Technology) (submittedVersion, cc-by)
- TUHH Open Research (cc-by)
- Funders
- European Molecular Biology Laboratory
- European Synchrotron Radiation Facility
- Centre National de la Recherche Scientifique
- Westfälische Wilhelms-Universität Münster
- Universität Hamburg
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme Catalysis and Immobilization
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- enzyme-substrate complex, lid domain, hydrophobic tunnel, substrate binding site, protein-substrate interactions, enzyme activity modulation, biocatalysis
- MeSH terms
- Protein Domains, Lipase, Monoacylglycerol Lipases, Catalytic Domain
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