6lwa

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Crystal structure of human NEIL1(P2G, E3Q, K242) bound to duplex DNA containing 5-hydroxyuracil (5-OHU)

Structural highlights

6lwa is a 9 chain structure with sequence from Escherichia coli and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.76Å
Ligands:OHU
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NEIL1_HUMAN Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Acts as DNA glycosylase that recognizes and removes damaged bases. Has a preference for oxidized pyrimidines, such as thymine glycol, formamidopyrimidine (Fapy) and 5-hydroxyuracil. Has marginal activity towards 8-oxoguanine. Has AP (apurinic/apyrimidinic) lyase activity and introduces nicks in the DNA strand. Cleaves the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates. Has DNA glycosylase/lyase activity towards mismatched uracil and thymine, in particular in U:C and T:C mismatches.[1] [2] [3] [4]

Publication Abstract from PubMed

DNA glycosylases must distinguish the sparse damaged sites from the vast expanse of normal DNA bases. However, our understanding of the nature of nucleobase interrogation is still limited. Here, we show that hNEIL1 (human endonuclease VIII-like 1) captures base lesions via two competing states of interaction: an activated state that commits catalysis and base excision repair, and a quarantine state that temporarily separates and protects the flipped base via auto-inhibition. The relative dominance of the two states depends on key residues of hNEIL1 and chemical properties (e.g. aromaticity and hydrophilicity) of flipped bases. Such a DNA repair mechanism allows hNEIL1 to recognize a broad spectrum of DNA damage while keeps potential gratuitous repair in check. We further reveal the molecular basis of hNEIL1 activity regulation mediated by post-transcriptional modifications and provide an example of how exquisite structural dynamics serves for orchestrated enzyme functions.

DNA repair glycosylase hNEIL1 triages damaged bases via competing interaction modes.,Liu M, Zhang J, Zhu C, Zhang X, Xiao W, Yan Y, Liu L, Zeng H, Gao YQ, Yi C Nat Commun. 2021 Jul 5;12(1):4108. doi: 10.1038/s41467-021-24431-y. PMID:34226550[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
0 reviews cite this structure
NEIL1 Recoding due to RNA Editing Impacts Lesion-Specific Recognition and Excision.
Lotsof et al. (2022)
-1 more
3 other articles
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See Also

References

  1. ↑ Takao M, Kanno S, Kobayashi K, Zhang QM, Yonei S, van der Horst GT, Yasui A. A back-up glycosylase in Nth1 knock-out mice is a functional Nei (endonuclease VIII) homologue. J Biol Chem. 2002 Nov 1;277(44):42205-13. Epub 2002 Aug 27. PMID:12200441 doi:http://dx.doi.org/10.1074/jbc.M206884200
  2. ↑ Bandaru V, Sunkara S, Wallace SS, Bond JP. A novel human DNA glycosylase that removes oxidative DNA damage and is homologous to Escherichia coli endonuclease VIII. DNA Repair (Amst). 2002 Jul 17;1(7):517-29. PMID:12509226
  3. ↑ Hazra TK, Izumi T, Boldogh I, Imhoff B, Kow YW, Jaruga P, Dizdaroglu M, Mitra S. Identification and characterization of a human DNA glycosylase for repair of modified bases in oxidatively damaged DNA. Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3523-8. PMID:11904416 doi:http://dx.doi.org/10.1073/pnas.062053799
  4. ↑ Dou H, Mitra S, Hazra TK. Repair of oxidized bases in DNA bubble structures by human DNA glycosylases NEIL1 and NEIL2. J Biol Chem. 2003 Dec 12;278(50):49679-84. Epub 2003 Sep 30. PMID:14522990 doi:http://dx.doi.org/10.1074/jbc.M308658200
  5. ↑ Liu M, Zhang J, Zhu C, Zhang X, Xiao W, Yan Y, Liu L, Zeng H, Gao YQ, Yi C. DNA repair glycosylase hNEIL1 triages damaged bases via competing interaction modes. Nat Commun. 2021 Jul 5;12(1):4108. PMID:34226550 doi:10.1038/s41467-021-24431-y

Contents


PDB ID 6lwa

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OCA

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