ArticleNucleic acids research2018
Regional conformational flexibility couples substrate specificity and scissile phosphate diester selectivity in human flap endonuclease 1.
Article in Nucleic acids research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 11 citations in OpenAlex.
- Functional roles for FEN1 phosphate steering residues in multi-step substrate verification prior to reaction.The Journal of biological chemistry · 2026Article
- Article
- Implementing fluorescence enhancement, quenching, and FRET for investigating flap endonuclease 1 enzymatic reaction at the single-molecule level.Computational and structural biotechnology journal · 2021Review
- The smfBox is an open-source platform for single-molecule FRET.Nature communications · 2020Article
- Recruiting Mechanism and Functional Role of a Third Metal Ion in the Enzymatic Activity of 5' Structure-Specific Nucleases.Journal of the American Chemical Society · 2020Article
- Resolution of the Holliday junction recombination intermediate by human GEN1 at the single-molecule level.Nucleic acids research · 2019Article
- A conserved loop-wedge motif moderates reaction site search and recognition by FEN1.Nucleic acids research · 2018Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
Human flap endonuclease-1 (hFEN1) catalyzes the divalent metal ion-dependent removal of single-stranded DNA protrusions known as flaps during DNA replication and repair. Substrate selectivity involves passage of the 5'-terminus/flap through the arch and recognition of a single nucleotide 3'-flap by the α2-α3 loop. Using NMR spectroscopy, we show that the solution conformation of free and DNA-bound hFEN1 are consistent with crystal structures; however, parts of the arch region and α2-α3 loop are disordered without substrate. Disorder within the arch explains how 5'-flaps can pass under it. NMR and single-molecule FRET data show a shift in the conformational ensemble in the arch and loop region upon addition of DNA. Furthermore, the addition of divalent metal ions to the active site of the hFEN1-DNA substrate complex demonstrates that active site changes are propagated via DNA-mediated allostery to regions key to substrate differentiation. The hFEN1-DNA complex also shows evidence of millisecond timescale motions in the arch region that may be required for DNA to enter the active site. Thus, hFEN1 regional conformational flexibility spanning a range of dynamic timescales is crucial to reach the catalytically relevant ensemble.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.