ENDO3c

endonuclease III

• SMART accession number: SM00478
• Description: includes endonuclease III (DNA-(apurinic or apyrimidinic site) lyase), alkylbase DNA glycosidases (Alka-family) and other DNA glycosidases
• Interpro abstract (IPR003265):

  Endonuclease III (EC 4.2.99.18) is a DNA repair enzyme which removes a number of damaged pyrimidines from DNA via its glycosylase activity and also cleaves the phosphodiester backbone at apurinic / apyrimidinic sites via a beta-elimination mechanism [(PUBMED:7773744), (PUBMED:9032058)]. The structurally related DNA glycosylase MutY recognises and excises the mutational intermediate 8-oxoguanine-adenine mispair [(PUBMED:1328155)]. The 3-D structures of Escherichia coli endonuclease III [(PUBMED:1411536)] and catalytic domain of MutY [(PUBMED:9846876)] have been determined. The structures contain two all-alpha domains: a sequence-continuous, six-helix domain (residues 22-132) and a Greek-key, four-helix domain formed by one N-terminal and three C-terminal helices (residues 1-21 and 133-211) together with the [Fe4S4] cluster. The cluster is bound entirely within the C-terminal loop by four cysteine residues with a ligation pattern Cys-(Xaa)6-Cys-(Xaa)2-Cys-(Xaa)5-Cys which is distinct from all other known Fe4S4 proteins. This structural motif is referred to as a [Fe4S4] cluster loop (FCL) [(PUBMED:7664751)]. Two DNA-binding motifs have been proposed, one at either end of the interdomain groove: the helix-hairpin-helix (HhH) and FCL motifs (see IPR003651). The primary role of the iron-sulphur cluster appears to involve positioning conserved basic residues for interaction with the DNA phosphate backbone by forming the loop of the FCL motif [(PUBMED:7664751), (PUBMED:10900127)].

  The HhH-GPD domain gets its name from its hallmark helix-hairpin-helix and Gly/Pro rich loop followed by a conserved aspartate. This domain is found in a diverse range of structurally related DNA repair proteins that include: endonuclease III, EC 4.2.99.18 and DNA glycosylase MutY, an A/G-specific adenine glycosylase. Both of these enzymes have a C-terminal iron-sulphur cluster loop (FCL). The methyl-CPG binding protein (MBD4) also contain a related domain that is a thymine DNA glycosylase. The family also includes DNA-3-methyladenine glycosylase II EC 3.2.2.21, 8-oxoguanine DNA glycosylases and other members of the AlkA family.

• GO process: base-excision repair (GO:0006284)

There are 5020 ENDO3c domains in 5020 proteins in SMART's nrdb database.

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Labahn J, Scharer OD, Long A, Ezaz-Nikpay K, Verdine GL, Ellenberger TE
• Structural basis for the excision repair of alkylation-damaged DNA.
• Cell. 1996; 86: 321-9

Base-excision DNA repair proteins that target alkylation damage act on a variety of seemingly dissimilar adducts, yet fail to recognize other closely related lesions. The 1.8 A crystal structure of the monofunctional DNA glycosylase AlkA (E. coli 3-methyladenine-DNA glycosylase II) reveals a large hydrophobic cleft unusually rich in aromatic residues. An Asp residue projecting into this cleft is essential for catalysis, and it governs binding specificity for mechanism-based inhibitors. We propose that AlkA recognizes electron-deficient methylated bases through pi-donor/acceptor interactions involving the electron-rich aromatic cleft. Remarkably, AlkA is similar in fold and active site location to the bifunctional glycosylase/lyase endonuclease III, suggesting the two may employ fundamentally related mechanisms for base excision.

• Yamagata Y et al.
• Three-dimensional structure of a DNA repair enzyme, 3-methyladenine DNA glycosylase II, from Escherichia coli.
• Cell. 1996; 86: 311-9

The three-dimensional structure of Escherichia coli 3-methyladenine DNA glycosylase II, which removes numerous alkylated bases from DNA, was solved at 2.3 A resolution. The enzyme consists of three domains: one alpha + beta fold domain with a similarity to one-half of the eukaryotic TATA box-binding protein, and two all alpha-helical domains similar to those of Escherichia coli endonuclease III with combined N-glycosylase/abasic lyase activity. Mutagenesis and model-building studies suggest that the active site is located in a cleft between the two helical domains and that the enzyme flips the target base out of the DNA duplex into the active-site cleft. The structure of the active site implies broad substrate specificity and simple N-glycosylase activity.

• Nakabeppu Y, Sekiguchi M
• Regulatory mechanisms for induction of synthesis of repair enzymes in response to alkylating agents: ada protein acts as a transcriptional regulator.
• Proc Natl Acad Sci U S A. 1986; 83: 6297-301

Expression of the ada and alkA genes, both of which are involved in the adaptive response of Escherichia coli to alkylating agents, is positively controlled by Ada protein, the product of the ada gene. Large amounts of ada- and alkA-specific RNA were formed in cells treated with a methylating agent, whereas little such RNA was produced in untreated cells. The in vivo transcription-initiation sites for the two genes were determined by primer-extension cDNA synthesis. In an in vitro reconstituted system, both ada and alkA transcripts were formed in an Ada protein-dependent manner. However, responses of the two transcription reactions to methylating agents differed; ada transcription was stimulated by methylnitrosourea, while alkA transcription was suppressed. We prepared a methylated form of Ada protein by an in vitro reaction and compared the activity with that of the normal, unmethylated form. The methylated form was more effective in promoting ada transcription than was the unmethylated form, but the effects of both forms were much the same with regard to alkA transcription. Based on these findings, we propose a model for the molecular mechanism of adaptive response.

Disease (disease genes where sequence variants are found in this domain)

SwissProt sequences and OMIM curated human diseases associated with missense mutations within the ENDO3c domain.

Protein	Disease
DNA-(apurinic or apyrimidinic site) lyase (O15527) (SMART)	OMIM:601982: Renal cell carcinoma, clear cell OMIM:144700:

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
100.00	map00240	Pyrimidine metabolism

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with ENDO3c domain which could be assigned to a KEGG orthologous group, and not all proteins containing ENDO3c domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of ENDO3c domains in PDB

PDB code	Title
1diz	Crystal structure of e. coli 3-methyladenine dna glycosylase (alka) complexed with dna
1ebm	Crystal structure of the human 8-oxoguanine glycosylase (hogg1) bound to a substrate oligonucleotide
1fn7	Coupling of damage recognition and catalysis by a human base-excision dna repair protein
1hu0	Crystal structure of an hogg1-dna borohydride trapped intermediate complex
1kea	Structure of a thermostable thymine-dna glycosylase
1kg2	Crystal structure of the core fragment of muty from e.coli at 1.2a resolution
1kg3	Crystal structure of the core fragment of muty from e.coli at 1.55a resolution
1kg4	Crystal structure of the k142a mutant of e. coli muty (core fragment)
1kg5	Crystal structure of the k142q mutant of e.coli muty (core fragment)
1kg6	Crystal structure of the k142r mutant of e.coli muty (core fragment)
1kg7	Crystal structure of the e161a mutant of e.coli muty (core fragment)
1ko9	Native structure of the human 8-oxoguanine dna glycosylase hogg1
1kqj	Crystal structure of a mutant of muty catalytic domain
1lwv	Borohydride-trapped hogg1 intermediate structure co- crystallized with 8-aminoguanine
1lww	Borohydride-trapped hogg1 intermediate structure co- crystallized with 8-bromoguanine
1lwy	Hogg1 borohydride-trapped intermediate without 8-oxoguanine
1m3h	Crystal structure of hogg1 d268e mutant with product oligonucleotide
1m3q	Crystal structure of hogg1 d268e mutant with base-excised dna and 8-aminoguanine
1mpg	3-methyladenine dna glycosylase ii from escherichia coli
1mud	Catalytic domain of muty from escherichia coli, d138n mutant complexed to adenine
1mun	Catalytic domain of muty from escherichia coli d138n mutant
1muy	Catalytic domain of muty from escherichia coli
1n39	Structural and biochemical exploration of a critical amino acid in human 8-oxoguanine glycosylase
1n3a	Structural and biochemical exploration of a critical amino acid in human 8-oxoguanine glycosylase
1n3c	Structural and biochemical exploration of a critical amino acid in human 8-oxoguanine glycosylase
1orn	Structure of a trapped endonuclease iii-dna covalent intermediate: estranged-guanine complex
1orp	Structure of a trapped endonuclease iii-dna covalent intermediate: estranged-adenine complex
1p59	Structure of a non-covalent endonuclease iii-dna complex
1pu6	Crystal structure of h.pylori 3-methyladenine dna glycosylase (magiii)
1pu7	Crystal structure of h.pylori 3-methyladenine dna glycosylase (magiii) bound to 3,9-dimethyladenine
1pu8	Crystal structure of h.pylori 3-methyladenine dna glycosylase (magiii) bound to 1,n6-ethenoadenine
1pvs	3-methyladenine glcosylase ii(alka) hypoxanthine complex
1rrq	Muty adenine glycosylase in complex with dna containing an a:oxog pair
1rrs	Muty adenine glycosylase in complex with dna containing an abasic site
1vrl	Muty adenine glycosylase in complex with dna and soaked adenine free base
1wef	Catalytic domain of muty from escherichia coli k20a mutant
1weg	Catalytic domain od muty form escherichia coli k142a mutant
1wei	Catalytic domain of muty from escherichia coli k20a mutant complexed to adenine
1yqk	Human 8-oxoguanine glycosylase crosslinked with guanine containing dna
1yql	Catalytically inactive hogg1 crosslinked with 7-deaza-8- azaguanine containing dna
1yqm	Catalytically inactive human 8-oxoguanine glycosylase crosslinked to 7-deazaguanine containing dna
1yqr	Catalytically inactive human 8-oxoguanine glycosylase crosslinked to oxog containing dna
2abk	Refinement of the native structure of endonuclease iii to a resolution of 1.85 angstrom
2csb	Crystal structure of topoisomerase v from methanopyrus kandleri (61 kda fragment)
2csd	Crystal structure of topoisomerase v (61 kda fragment)
2h56	Crystal structure of dna-3-methyladenine glycosidase (10174367) from bacillus halodurans at 2.55 a resolution
2i5w	Structure of hogg1 crosslinked to dna sampling a normal g adjacent to an oxog
2jhj	3-methyladenine dna-glycosylase from archaeoglobus fulgidus
2jhn	3-methyladenine dna-glycosylase from archaeoglobus fulgidus
2nob	Structure of catalytically inactive h270a human 8- oxoguanine glycosylase crosslinked to 8-oxoguanine dna
2noe	Structure of catalytically inactive g42a human 8-oxoguanine glycosylase complexed to 8-oxoguanine dna
2nof	Structure of q315f human 8-oxoguanine glycosylase proximal crosslink to 8-oxoguanine dna
2noh	Structure of catalytically inactive q315a human 8- oxoguanine glycosylase complexed to 8-oxoguanine dna
2noi	Structure of g42a human 8-oxoguanine glycosylase crosslinked to undamaged g-containing dna
2nol	Structure of catalytically inactive human 8-oxoguanine glycosylase distal crosslink to oxog dna
2noz	Structure of q315f human 8-oxoguanine glycosylase distal crosslink to 8-oxoguanine dna
3cvs	Crystal structure of an alka host/guest complex 8oxoguanine:adenine base pair
3cvt	Crystal structure of an alka host/guest complex 8oxoguanine:cytosine base pair
3cw7	Crystal structure of an alka host/guest complex 8oxoguanine:cytosine base pair
3cwa	Crystal structure of an alka host/guest complex 8oxoguanine:cytosine base pair
3cws	Crystal structure of an alka host/guest complex 2'-fluoro- 2'-deoxyinosine:thymine base pair
3cwt	Crystal structure of an alka host/guest complex 2'-fluoro- 2'-deoxyinosine:adenine base pair
3cwu	Crystal structure of an alka host/guest complex 2'-fluoro- 2'-deoxy-1,n6-ethenoadenine:thymine base pair
3d4v	Crystal structure of an alka host/guest complex n7methylguanine:cytosine base pair
3f0z	Crystal structure of clostridium acetobutylicum 8- oxoguanine glycosylase/lyase in its apo-form
3f10	Crystal structure of clostridium acetobutylicum 8- oxoguanine dna glycosylase in complex with 8-oxoguanosine
3fhf	Crystal structure of methanocaldococcus jannaschii 8- oxoguanine dna glycosylase (mjogg)
3fhg	Crystal structure of sulfolobus solfataricus 8-oxoguanine dna glycosylase (ssogg)
3g0q	Crystal structure of muty bound to its inhibitor dna
3i0w	Crystal structure of clostridium acetobutylicum 8-oxoguanine glycosylase/lyase in complex with dsdna containing cytosine opposite to 8-oxog
3i0x	Crystal structure of clostridium acetobutylicum 8-oxoguanine glycosylase/lyase in complex with dsdna containing adenine opposite to 8-oxog

Links (links to other resources describing this domain)

• PFAM: AlkA_DNA_repair
• INTERPRO: IPR003265
• PROSITE: ENDONUCLEASE_III_2