Letunic et al. (2017) Nucleic Acids Res doi: 10.1093/nar/gkx922
Letunic et al. (2020) Nucleic Acids Res doi: 10.1093/nar/gkaa937

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HNHc HNH nucleases

SMART accession number:	SM00507
Description:	-
Interpro abstract (IPR003615):	This domain is found in HNH family of nucleases that includes yeast intron 1 protein, MutS, and bacterial colicins, pyocins and endonuclease HphI. They are found in bacteria, viruses and eukaryotes.
Family alignment:	View or CHROMA formatHMM/Web logoCLUSTALW formatMSF formatFASTA formatPIR format

There are 90127 HNHc domains in 89843 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Taxonomic distribution of proteins containing HNHc domain.

  This tree includes only several representative species. The complete taxonomic breakdown of all proteins with HNHc domain is also avaliable.

  Click on the protein counts, or double click on taxonomic names to display all proteins containing HNHc domain in the selected taxonomic class.

• Literature (relevant references for this domain)

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

  • Kleanthous C et al.
  • Structural and mechanistic basis of immunity toward endonuclease colicins.
  • Nat Struct Biol. 1999; 6: 243-52
  • Display abstract

  • The crystal structure of the cytotoxic endonuclease domain from the bacterial toxin colicin E9 in complex with its cognate immunity protein Im9 reveals that the inhibitor does not bind at the active site, the core of which comprises the HNH motif found in intron-encoded homing endonucleases, but rather at an adjacent position leaving the active site exposed yet unable to bind DNA because of steric and electrostatic clashes with incoming substrate. Although its mode of action is unorthodox, Im9 is a remarkably effective inhibitor since it folds within milliseconds and then associates with its target endonuclease at the rate of diffusion to form an inactive complex with sub-femtomolar binding affinity. This hyperefficient mechanism of inhibition could be well suited to other toxic enzyme systems, particularly where the substrate is a polymer extending beyond the boundaries of the active site.

  • Dalgaard JZ, Klar AJ, Moser MJ, Holley WR, Chatterjee A, Mian IS
  • Statistical modeling and analysis of the LAGLIDADG family of site-specific endonucleases and identification of an intein that encodes a site-specific endonuclease of the HNH family.
  • Nucleic Acids Res. 1997; 25: 4626-38
  • Display abstract

  • The LAGLIDADG and HNH families of site-specific DNA endonucleases encoded by viruses, bacteriophages as well as archaeal, eucaryotic nuclear and organellar genomes are characterized by the sequence motifs 'LAGLIDADG' and 'HNH', respectively. These endonucleases have been shown to occur in different environments: LAGLIDADG endonucleases are found in inteins, archaeal and group I introns and as free standing open reading frames (ORFs); HNH endonucleases occur in group I and group II introns and as ORFs. Here, statistical models (hidden Markov models, HMMs) that encompass both the conserved motifs and more variable regions of these families have been created and employed to characterize known and potential new family members. A number of new, putative LAGLIDADG and HNH endonucleases have been identified including an intein-encoded HNH sequence. Analysis of an HMM-generated multiple alignment of 130 LAGLIDADG family members and the three-dimensional structure of the I- Cre I endonuclease has enabled definition of the core elements of the repeated domain (approximately 90 residues) that is present in this family of proteins. A conserved negatively charged residue is proposed to be involved in catalysis. Phylogenetic analysis of the two families indicates a lack of exchange of endonucleases between different mobile elements (environments) and between hosts from different phylogenetic kingdoms. However, there does appear to have been considerable exchange of endonuclease domains amongst elements of the same type. Such events are suggested to be important for the formation of elements of new specficity.

  • Gorbalenya AE
  • Self-splicing group I and group II introns encode homologous (putative) DNA endonucleases of a new family.
  • Protein Sci. 1994; 3: 1117-20
  • Display abstract

  • A new family of protein domains consisting of 50-80 amino acid residues is described. It is composed of nearly 40 members, including domains encoded by plastid and phage group I introns; mitochondrial, plastid, and bacterial group II introns; eubacterial genomes and plasmids; and phages. The name "EX1HH-HX3H" was coined for both domain and family. It is based on 2 most prominent amino acid sequence motifs, each encompassing a pair of highly conserved histidine residues in a specific arrangement: EX1HH and HX3H. The "His" motifs often alternate with amino- and carboxy-terminal motifs of a new type of Zn-finger-like structure CX2,4CX29-54[CH]X2,3[CH]. The EX1HH-HX3H domain in eubacterial E2-type bacteriocins and in phage RB3 (wild variant of phage T4) product of the nrdB group I intron was reported to be essential for DNA endonuclease activity of these proteins. In other proteins, the EX1HH-HX3H domain is hypothesized to possess DNase activity as well. Presumably, this activity promotes movement (rearrangement) of group I and group II introns encoding the EX1HH-HX3H domain and other gene targets. In the case of Escherichia coli restrictase McrA and possibly several related proteins, it appears to mediate the restriction of alien DNA molecules.

  • Shub DA, Goodrich-Blair H, Eddy SR
  • Amino acid sequence motif of group I intron endonucleases is conserved in open reading frames of group II introns.
  • Trends Biochem Sci. 1994; 19: 402-4
• Structure (3D structures containing this domain)

• 3D Structures of HNHc domains in PDB

  PDB code	Main view	Title
  1bxi		CRYSTAL STRUCTURE OF THE ESCHERICHIA COLI COLICIN E9 DNASE DOMAIN WITH ITS COGNATE IMMUNITY PROTEIN IM9
  1emv		CRYSTAL STRUCTURE OF COLICIN E9 DNASE DOMAIN WITH ITS COGNATE IMMUNITY PROTEIN IM9 (1.7 ANGSTROMS)
  1fr2		CRYSTAL STRUCTURE OF THE E9 DNASE DOMAIN WITH A MUTANT IMMUNITY PROTEIN IM9(E41A)
  1fsj		CRYSTAL STRUCTURE OF THE E9 DNASE DOMAIN
  1m08		Crystal structure of the unbound nuclease domain of ColE7
  1mz8		CRYSTAL STRUCTURES OF THE NUCLEASE DOMAIN OF COLE7/IM7 IN COMPLEX WITH A PHOSPHATE ION AND A ZINC ION
  1pt3		Crystal structures of nuclease-ColE7 complexed with octamer DNA
  1u3e		DNA binding and cleavage by the HNH homing endonuclease I-HmuI
  1ujz		Crystal structure of the E7_C/Im7_C complex; a computationally designed interface between the colicin E7 DNase and the Im7 Immunity protein
  1v13		CRYSTAL STRUCTURE OF THE MUTANT HIS103ALA OF THE COLICIN E9 DNASE DOMAIN IN COMPLEX WITH ZN+2 (2.0 ANGSTROMS)
  1v14		Crystal Structure of the Colicin E9, mutant His103Ala, in complex with Mg+2 and dsDNA (resolution 2.9A)
  1v15		CRYSTAL STRUCTURE OF THE COLICIN E9, MUTANT HIS103ALA, IN COMPLEX WITH ZN+2 AND DSDNA (RESOLUTION 2.4A)
  1zns		Crystal structure of N-ColE7/12-bp DNA/Zn complex
  1znv		How a His-metal finger endonuclease ColE7 binds and cleaves DNA with a transition metal ion cofactor
  2erh		Crystal Structure of the E7_G/Im7_G complex; a designed interface between the colicin E7 DNAse and the Im7 immunity protein
  2gyk		Crystal structure of the complex of the Colicin E9 DNase domain with a mutant immunity protein, IMME9 (D51A)
  2gze		Crystal structure of the E9 DNase domain with a mutant immunity protein IM9 (Y55A)
  2gzf		Crystal structure of the E9 DNase domain with a mutant immunity protein IM9 (Y54F)
  2gzg		Crystal Structure of the E9 DNase Domain with a Mutant Immunity Protein IM9 (Y55F)
  2gzi		Crystal Structure of the E9 DNase Domain with a Mutant Immunity Protein IM9 (V34A)
  2gzj		Crystal Structure of the E9 DNase Domain with a Mutant Immunity Protein IM9 (D51A)
  2ivh		Crystal structure of the nuclease domain of ColE7 (H545Q mutant) in complex with an 18-bp duplex DNA
  2jaz		CRYSTAL STRUCTURE OF THE MUTANT N560D OF THE NUCLEASE DOMAIN OF COLE7 IN COMPLEX WITH IM7
  2jb0		CRYSTAL STRUCTURE OF THE MUTANT H573A OF THE NUCLEASE DOMAIN OF COLE7 IN COMPLEX WITH IM7
  2jbg		crystal structure of the mutant N560A of the nuclease domain of ColE7 in complex with Im7
  2k5x		Chemical shift structure of COLICIN E9 DNASE domain with its cognate immunity protein IM9
  2vln		N75A mutant of E9 DNase domain in complex with Im9
  2vlo		K97A mutant of E9 DNase domain in complex with Im9
  2vlp		R54A mutant of E9 DNase domain in complex with Im9
  2vlq		F86A mutant of E9 DNase domain in complex with Im9
  2wpt		The crystal structure of Im2 in complex with colicin E9 DNase
  3fbd		Crystal structure of the nuclease domain of COLE7(D493Q mutant) in complex with an 18-BP duplex DNA
  3gjn		Following evolutionary paths to high affinity and selectivity protein-protein interactions using Colicin7 and Immunity proteins
  3gkl		Following evolutionary paths to high affinity and selectivity protein-protein interactions using Colicin7 and Immunity proteins
  3u43		Crystal structure of the colicin E2 DNase-Im2 complex
  3zfk		N-terminal truncated Nuclease Domain of Colicin E7
  4cmp		Crystal structure of S. pyogenes Cas9
  4cmq		Crystal structure of Mn-bound S.pyogenes Cas9
  4h9d		Crystal Structure of Mn-dependent Gme HNH nicking endonuclease from Geobacter metallireducens GS-15, Northeast Structural Genomics Consortium (NESG) Target GmR87
  4ogc		Crystal structure of the Type II-C Cas9 enzyme from Actinomyces naeslundii
  4oge		Crystal structure of the Type II-C Cas9 enzyme from Actinomyces naeslundii
  4qko		4QKO
  4uhp		4UHP
  4uhq		4UHQ
  4zt0		4ZT0
  5b2o		5B2O
  5b2p		5B2P
  5b2q		5B2Q
  5ew5		5EW5
  5f9r		5F9R
  5g2x		5G2X
  7cei		THE ENDONUCLEASE DOMAIN OF COLICIN E7 IN COMPLEX WITH ITS INHIBITOR IM7 PROTEIN

• Links (links to other resources describing this domain)

• INTERPRO	IPR003615

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