8jnr

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Crystal structure of human ALKBH3 bound to 3mC containing ssDNA through distal crosslink

Structural highlights

8jnr is a 14 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.66Å
Ligands:ME6, MN, OGA
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ALKB3_HUMAN Dioxygenase that mediates demethylation of DNA and RNA containing 1-methyladenosine (m1A) (PubMed:12486230, PubMed:12594517, PubMed:16174769, PubMed:26863196, PubMed:26863410). Repairs alkylated DNA containing 1-methyladenosine (m1A) and 3-methylcytosine (m3C) by oxidative demethylation (PubMed:12486230, PubMed:12594517, PubMed:16174769, PubMed:25944111). Has a strong preference for single-stranded DNA (PubMed:12486230, PubMed:12594517, PubMed:16174769, PubMed:20714506). Able to process alkylated m3C within double-stranded regions via its interaction with ASCC3, which promotes DNA unwinding to generate single-stranded substrate needed for ALKBH3 (PubMed:22055184). Can repair exocyclic 3,N4-ethenocytosine adducs in single-stranded DNA (PubMed:25797601). Also acts on RNA (PubMed:12594517, PubMed:16174769, PubMed:16858410, PubMed:26863196, PubMed:26863410). Demethylates N(1)-methyladenosine (m1A) RNA, an epigenetic internal modification of messenger RNAs (mRNAs) highly enriched within 5'-untranslated regions (UTRs) and in the vicinity of start codons (PubMed:26863196, PubMed:26863410). Requires molecular oxygen, alpha-ketoglutarate and iron (PubMed:16858410, PubMed:22055184).[1] [2] [3] [4] [5] [6] [7] [8] [9]

Publication Abstract from PubMed

N(1) -methyladenosine (m(1) A) is a prevalent post-transcriptional RNA modification, and the distribution and dynamics of the modification play key epitranscriptomic roles in cell development. At present, the human AlkB Fe(II)/alpha-ketoglutarate-dependent dioxygenase family member ALKBH3 is the only known mRNA m(1) A demethylase, but its catalytic mechanism remains unclear. Here, we present the structures of ALKBH3-oligo crosslinked complexes obtained with the assistance of a synthetic antibody crystallization chaperone. Structural and biochemical results showed that ALKBH3 utilized two beta-hairpins (beta4-loop-beta5 and beta'-loop-beta) and the alpha2 helix to facilitate single-stranded substrate binding. Moreover, a bubble-like region around Asp194 and a key residue inside the active pocket (Thr133) enabled specific recognition and demethylation of m(1) A- and 3-methylcytidine (m(3) C)-modified substrates. Mutation of Thr133 to the corresponding residue in the AlkB Fe(II)/alpha-ketoglutarate-dependent dioxygenase family members FTO or ALKBH5 converted ALKBH3 substrate selectivity from m(1) A to N(6) -methyladenosine (m(6) A), as did Asp194 deletion. Our findings provide a molecular basis for understanding the mechanisms of substrate recognition and m(1) A demethylation by ALKBH3. This study is expected to aid structure-guided design of chemical probes for further functional studies and therapeutic applications.

The Molecular Basis of Human ALKBH3 Mediated RNA N(1) -methyladenosine (m(1) A) Demethylation.,Zhang L, Duan HC, Paduch M, Hu J, Zhang C, Mu Y, Lin H, He C, Kossiakoff AA, Jia G, Zhang L Angew Chem Int Ed Engl. 2024 Feb 12;63(7):e202313900. doi: , 10.1002/anie.202313900. Epub 2024 Jan 11. PMID:38158383[10]

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

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Citations
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Writers, readers, and erasers RNA modifications and drug resistance in cancer.
Chen et al. (2024)
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References

  1. ↑ Duncan T, Trewick SC, Koivisto P, Bates PA, Lindahl T, Sedgwick B. Reversal of DNA alkylation damage by two human dioxygenases. Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16660-5. Epub 2002 Dec 16. PMID:12486230 doi:10.1073/pnas.262589799
  2. ↑ Aas PA, Otterlei M, Falnes PO, Vagbo CB, Skorpen F, Akbari M, Sundheim O, Bjoras M, Slupphaug G, Seeberg E, Krokan HE. Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA. Nature. 2003 Feb 20;421(6925):859-63. PMID:12594517 doi:10.1038/nature01363
  3. ↑ Lee DH, Jin SG, Cai S, Chen Y, Pfeifer GP, O'Connor TR. Repair of methylation damage in DNA and RNA by mammalian AlkB homologues. J Biol Chem. 2005 Nov 25;280(47):39448-59. Epub 2005 Sep 20. PMID:16174769 doi:M509881200
  4. ↑ Sundheim O, Vagbo CB, Bjoras M, Sousa MM, Talstad V, Aas PA, Drablos F, Krokan HE, Tainer JA, Slupphaug G. Human ABH3 structure and key residues for oxidative demethylation to reverse DNA/RNA damage. EMBO J. 2006 Jul 26;25(14):3389-97. Epub 2006 Jul 6. PMID:16858410
  5. ↑ Dango S, Mosammaparast N, Sowa ME, Xiong LJ, Wu F, Park K, Rubin M, Gygi S, Harper JW, Shi Y. DNA unwinding by ASCC3 helicase is coupled to ALKBH3-dependent DNA alkylation repair and cancer cell proliferation. Mol Cell. 2011 Nov 4;44(3):373-84. PMID:22055184 doi:10.1016/j.molcel.2011.08.039
  6. ↑ Zdżalik D, Domańska A, Prorok P, Kosicki K, van den Born E, Falnes PØ, Rizzo CJ, Guengerich FP, Tudek B. Differential repair of etheno-DNA adducts by bacterial and human AlkB proteins. DNA Repair (Amst). 2015 Jun;30:1-10. PMID:25797601 doi:10.1016/j.dnarep.2015.02.021
  7. ↑ Zhao Y, Majid MC, Soll JM, Brickner JR, Dango S, Mosammaparast N. Noncanonical regulation of alkylation damage resistance by the OTUD4 deubiquitinase. EMBO J. 2015 Jun 12;34(12):1687-703. doi: 10.15252/embj.201490497. Epub 2015 May , 5. PMID:25944111 doi:http://dx.doi.org/10.15252/embj.201490497
  8. ↑ Dominissini D, Nachtergaele S, Moshitch-Moshkovitz S, Peer E, Kol N, Ben-Haim MS, Dai Q, Di Segni A, Salmon-Divon M, Clark WC, Zheng G, Pan T, Solomon O, Eyal E, Hershkovitz V, Han D, Doré LC, Amariglio N, Rechavi G, He C. The dynamic N(1)-methyladenosine methylome in eukaryotic messenger RNA. Nature. 2016 Feb 25;530(7591):441-6. PMID:26863196 doi:10.1038/nature16998
  9. ↑ Li X, Xiong X, Wang K, Wang L, Shu X, Ma S, Yi C. Transcriptome-wide mapping reveals reversible and dynamic N(1)-methyladenosine methylome. Nat Chem Biol. 2016 May;12(5):311-6. PMID:26863410 doi:10.1038/nchembio.2040
  10. ↑ Zhang L, Duan HC, Paduch M, Hu J, Zhang C, Mu Y, Lin H, He C, Kossiakoff AA, Jia G, Zhang L. The Molecular Basis of Human ALKBH3 Mediated RNA N(1) -methyladenosine (m(1) A) Demethylation. Angew Chem Int Ed Engl. 2024 Feb 12;63(7):e202313900. PMID:38158383 doi:10.1002/anie.202313900

Contents


PDB ID 8jnr

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