Uncovering an allosteric mode of action for a selective inhibitor of human Bloom syndrome protein
Open accessPublished version of a preprint
Abstract
BLM (Bloom syndrome protein) is a RECQ-family helicase involved in the dissolution of complex DNA structures and repair intermediates. Synthetic lethality analysis implicates BLM as a promising target in a range of cancers with defects in the DNA damage response; however, selective small molecule inhibitors of defined mechanism are currently lacking. Here, we identify and characterise a specific inhibitor of BLM’s ATPase-coupled DNA helicase activity, by allosteric trapping of a DNA-bound translocation intermediate. Crystallographic structures of BLM-DNA-ADP-inhibitor complexes identify a hitherto unknown interdomain interface, whose opening and closing are integral to translocation of ssDNA, and which provides a highly selective pocket for drug discovery. Comparison with structures of other RECQ helicases provides a model for branch migration of Holliday junctions by BLM.
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Allosteric drugs have higher specificity and lower toxicity due to targeting nonconserved allosteric sites.
“Due to its higher specificity and consequently lower toxicity, which results from targeting nonconserved allosteric sites, allostery also increasingly features in allosteric drugs.”
From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [123]
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References 43 · Cited by 34
- Authors
- Chen, X., Ali, Y. I., Fisher, C. E., Arribas-Bosacoma, R., Rajasekaran, M. B., Williams, G., Walker, S., Booth, J. R., Hudson, J. J., Roe, S. M., Pearl, L. H., Ward, S. E., Pearl, F. M., & Oliver, A. W.
- Affiliations
- University of Sussex (GB)
- Corresponding author
- Ward, Simon E
- Pearl, Frances MG
- Oliver, Antony W
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2021-03-01
- Volume
- 10
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC7924943
- OpenAlex
- W3133610613
- Cited by
- 34
- References
- 43
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 8 · 2023: 5 · 2022: 7 · 2021: 2
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Cancer Research UK (C302/A24386)
- China Scholarship Council
- Wellcome (105630/Z/14/Z, 110578/Z/15/Z)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- Bloom syndrome protein, BLM, RecQ helicase, allosteric inhibition, interdomain interface, DNA damage response, synthetic lethality, cancer drug targets
- MeSH terms
- DNA, DNA, Single-Stranded, Enzyme Inhibitors, Escherichia coli, Humans, DNA, Cruciform, RecQ Helicases, Small Molecule Libraries, Drug Discovery, High-Throughput Screening Assays
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