FES

• SMART accession number: SM00525
• Description: iron-sulpphur binding domain in DNA-(apurinic or apyrimidinic site) lyase (subfamily of ENDO3)
• Interpro abstract (IPR003651):

  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. 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 iron-sulphur cluster loop (FCL) is also found in DNA-(apurinic or apyrimidinic site) lyase, a subfamily of endonuclease III. The enzyme has both apurinic and apyrimidinic endonuclease activity and a DNA N-glycosylase activity. It cuts damaged DNA at cytosines, thymines and guanines, and acts on the damaged strand 5' of the damaged site. The enzyme binds a 4Fe-4S cluster which is not important for the catalytic activity, but is probably involved in the alignment of the enzyme along the DNA strand.

• GO function: 4 iron, 4 sulfur cluster binding (GO:0051539), endonuclease activity (GO:0004519)

There are 2821 FES domains in 2802 proteins in SMART's nrdb database.

Literature (relevant references for this domain)

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

• Chepanoske CL, Golinelli MP, Williams SD, David SS
• Positively charged residues within the iron-sulfur cluster loop of E. coli MutY participate in damage recognition and removal.
• Arch Biochem Biophys. 2000; 380: 11-9

Escherichia coli MutY is an adenine glycosylase involved in base excision repair that recognizes OG:A (where OG = 7, 8-dihydro-8-oxo-2'-deoxyguanosine) and G:A mismatches in DNA. MutY contains a solvent-exposed polypeptide loop between two of the cysteine ligands to the [4Fe-4S](2+) cluster, referred to as the iron-sulfur cluster loop (FCL) motif. The FCL is located adjacent to the proposed active site pocket and has been suggested to be part of the DNA binding surface of MutY (Y. Guan et al., 1998, Nat. Struct. Biol. 5, 1058-1064). In order to investigate the role of specific residues within the FCL motif, we have determined the effects of replacing arginine 194, lysine 196, and lysine 198 with alanine on the enzymatic properties of MutY. The properties of the R194A, K196A, and K198A enzymes were also compared to the properties of mutated enzymes in which lysine residues near the active site pocket were replaced with alanine or glycine. Substrate recognition was evaluated using a duplex containing a 2'-deoxyadenosine analog in a base pair opposite G or OG. These results indicate that removal of positively charged amino acids within the FCL and the active site compromise the ability of the enzyme to bind to the substrate analog. However, only the K198A enzyme exhibited a significant reduction (15-fold) of the rate of adenine removal from a G:A base pair-containing duplex. This is the first direct evidence that Lys 198 within the FCL motif of MutY has a role in specific damage recognition and removal. Furthermore, these results suggest that the FCL motif is intimately involved in the base removal process.

• Tainer JA, Thayer MM, Cunningham RP
• DNA repair proteins.
• Curr Opin Struct Biol. 1995; 5: 20-6

DNA repair proteins act to correct mutagenic and toxic DNA damage, which can lead to cancer, aging and death. These proteins and their mechanisms of action have been found to be widely conserved between species, often from bacteria to man. Structural and biochemical studies on several bacterial enzymes involved in direct reversal and base excision repair have provided insights into the molecular basis of the recognition of damaged DNA and have also highlighted the novel roles that transition metals play in DNA repair.

• Kuo CF, McRee DE, Fisher CL, O'Handley SF, Cunningham RP, Tainer JA
• Atomic structure of the DNA repair [4Fe-4S] enzyme endonuclease III.
• Science. 1992; 258: 434-40

The crystal structure of the DNA repair enzyme endonuclease III, which recognizes and cleaves DNA at damaged bases, has been solved to 2.0 angstrom resolution with an R factor of 0.185. This iron-sulfur [4Fe-4S] enzyme is elongated and bilobal with a deep cleft separating two similarly sized domains: a novel, sequence-continuous, six-helix domain (residues 22 to 132) and a Greek-key, four-helix domain formed by the amino-terminal and three carboxyl-terminal helices (residues 1 to 21 and 133 to 211) together with the [4Fe-4S] cluster. The cluster is bound entirely within the carboxyl-terminal loop with a ligation pattern (Cys-X6-Cys-X2-Cys-X5-Cys) distinct from all other known [4Fe-4S] proteins. Sequence conservation and the positive electrostatic potential of conserved regions identify a surface suitable for binding duplex B-DNA across the long axis of the enzyme, matching a 46 angstrom length of protected DNA. The primary role of the [4Fe-4S] cluster appears to involve positioning conserved basic residues for interaction with the DNA phosphate backbone. The crystallographically identified inhibitor binding region, which recognizes the damaged base thymine glycol, is a seven-residue beta-hairpin (residues 113 to 119). Location and side chain orientation at the base of the inhibitor binding site implicate Glu112 in the N-glycosylase mechanism and Lys120 in the beta-elimination mechanism. Overall, the structure reveals an unusual fold and a new biological function for [4Fe-4S] clusters and provides a structural basis for studying recognition of damaged DNA and the N-glycosylase and apurinic/apyrimidinic-lyase mechanisms.

Structure (3D structures containing this domain)

3D Structures of FES domains in PDB

PDB code	Title
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)
1kqj	Crystal structure of a mutant of muty catalytic domain
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
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
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
2abk	Refinement of the native structure of endonuclease iii to a resolution of 1.85 angstrom
3g0q	Crystal structure of muty bound to its inhibitor dna

Links (links to other resources describing this domain)

• PFAM: Endonuclease_3
• INTERPRO: IPR003651
• PROSITE: ENDONUCLEASE_III_1