ArticleNucleic acids research2018
Snapshots of an evolved DNA polymerase pre- and post-incorporation of an unnatural nucleotide.
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 14 papers.
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Who cites it
14 citing papers in PubMed.
- Derivatives of dPMTO, dMTMO, and dTPT3 as efficient genetic alphabets for artificial DNA.Journal of molecular modeling · 2026Article
- Recognition of non-standard base pairs by triplex-forming oligonucleotides containing an expanded genetic alphabet.Nature communications · 2026Article
- Recognition of Non-standard Base Pairs by Triplex-Forming Oligonucleotides Containing an Expanded Genetic Alphabet.Research square · 2026Article
- Engineering and Assay of Enzymes for Expanded Genetic Alphabet Replication.Biochemistry · 2025Article
- Cancer cell target discovery: comparing laboratory evolution of expanded DNA six-nucleotide alphabets with standard four-nucleotide alphabets.Nucleic acids research · 2025Article
- Nucleic acid joining enzymes: biological functions and synthetic applications beyond DNA.The Biochemical journal · 2025Review
- Enzymatic synthesis and nanopore sequencing of 12-letter supernumerary DNA.Nature communications · 2023Article
- Fragment- and structure-based drug discovery for developing therapeutic agents targeting the DNA Damage Response.Progress in biophysics and molecular biology · 2021Article
- Building better polymerases: Engineering the replication of expanded genetic alphabets.The Journal of biological chemistry · 2020Review
- Review
- The Structural Basis for Processing of Unnatural Base Pairs by DNA Polymerases.Chemistry (Weinheim an der Bergstrasse, Germany) · 2020Review
- Building better enzymes: Molecular basis of improved non-natural nucleobase incorporation by an evolved DNA polymerase.Protein science : a publication of the Protein Society · 2020Article
- Hachimoji DNA and RNA: A genetic system with eight building blocks.Science (New York, N.Y.) · 2019Article
- Article
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
The next challenge in synthetic biology is to be able to replicate synthetic nucleic acid sequences efficiently. The synthetic pair, 2-amino-8-(1-beta-d-2'- deoxyribofuranosyl) imidazo [1,2-a]-1,3,5-triazin-[8H]-4-one (trivially designated P) with 6-amino-3-(2'-deoxyribofuranosyl)-5-nitro-1H-pyridin-2-one (trivially designated Z), is replicated by certain Family A polymerases, albeit with lower efficiency. Through directed evolution, we identified a variant KlenTaq polymerase (M444V, P527A, D551E, E832V) that incorporates dZTP opposite P more efficiently than the wild-type enzyme. Here, we report two crystal structures of this variant KlenTaq, a post-incorporation complex that includes a template-primer with P:Z trapped in the active site (binary complex) and a pre-incorporation complex with dZTP paired to template P in the active site (ternary complex). In forming the ternary complex, the fingers domain exhibits a larger closure angle than in natural complexes but engages the template-primer and incoming dNTP through similar interactions. In the binary complex, although many of the interactions found in the natural complexes are retained, there is increased relative motion of the thumb domain. Collectively, our analyses suggest that it is the post-incorporation complex for unnatural substrates that presents a challenge to the natural enzyme and that more efficient replication of P:Z pairs requires a more flexible polymerase.
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