To this connection. Based on the information of

To achieve specificity in DNA-binding
interaction, the accommodation of the protein three dimensional structures with
the DNA three dimensional structures in the binding site are required (Schneider
et al. 2014). Also, all the amino acids existing at the interaction site do not
establish a biochemical binding with DNA molecules. Some of the amino acids
have a very especial and important binding role while others have a limited or
no role in this connection. Based on the information of database (database of
binding pairs in protein-nucleic acid interactions) and study of the
log-likelihood, the tendency of the amino acids’ becoming or not becoming a
bond and the probability of their cooperation in the interaction sites with DNA
has been shown ().

Proteins possess a lot of DNA-binding
motifs that are able to mediate many important specific and non-specific
interactions. Based on the classification of SCOP database, DNA-binding
proteins are classified in more than 70 super families (Rohs et al. 2010).
These proteins are divided based on the secondary structure of DNA-binding
consensus regions to groups with ?-helix structure, ?-sheet, ?-? mixture,
combination of several regions (a mixture of more than one type of region and
their binding structures). Up to date, many DNA-binding protein motifs were
identified by X-ray crystallography and have been deposited in the Protein Data
Bank (PDB). DNA-binding classification based on the DNA-binding motif classify
proteins with the same DNA-binding motif into same clusters suggesting that the
motif-based classification of DNA-binding proteins may not necessarily correspond their
structural and functional properties characterizing protein-DNA recognition (Tripathi
and Gupta 2013). In this section, we will focus on the major groups of
DNA-binding motifs that members of them share same structural features in
bounding DNA molecule (for more details see Luscombe et al., 2000; Rohs et al
2012).

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Helix-Turn-Helix (HTH) motif: Helix-Turn-Helix (HTH) DNA-binding motif
is one of the predominant structural DNA-binding motifs that are seen in many
DNA-binding proteins belonging to different SCOP super families (Posinski et
al. 1999). For example, HTH DNA binding domain was identified in Transcription
Factors and Enzymes from prokaryotes to eukaryotes (Luscombe et al., 2000). However,
the structure of the HTH motif in the DNA-binding proteins are structural
conserved in containing proteins, the structure outside the HTH motif region in
the protein are greatly different in the various HTH containing proteins (Jones
et al. 2003). Helix-turn-helix motif contain a 20-amino acid segment of two
almost perpendicular alpha helix connected by a four-amino acid containing beta
turn. However, the longer linkers such as loops were observed in different HTH
motif containing proteins. Sequence variety between HTH structural motifs in
functionally diverse proteins allows them to recognize distinct set of DNA
sequences (Luscombe et al. 2000). In HTH structural motif, the first alpha
helix refers as the probe helix and plays a stabilizer role in the interaction
between the protein and the DNA. The second alpha helix recognizes the
DNA-binding site and referred as recognition or probe helix (Pellegrini-Calacer
et al. 2005). It binds the DNA-binding site through a series of hydrogen bonds
and hydrophobic interaction with the DNA major groove in exposed bases. It is
observed that the NH2-terminal end of the recognition helix pointed into the
major groove and no base-specific contact were shown within the minor groove (Schleif
1988). However, in some exceptional examples such as O6-alkylgunanine-DNA alkyl
transferase, HTH structural motifs are intact to minor groove (Daniels et al.
2004). Also, the recognition helix supports the contact with the DNA backbone
as the linker made it (Propper et al. 2014). HTH motifs is part of a
DNA-binding protein and amino acid residues outside the HTH motif play the
important role in regulating DNA recognition and binding (Pllegrini-Calace et
al. 2005; Yesudhas et al. 2017). Also, additional alpha helix and its adjacent
beta sheet to HTH motif extended the HTH structural motif to Winged
Helix-Turn-Helix (wHTH) motif which is considered as components of the HTH-DNA-binding motif (Teichmann et
al. 2012). The extra secondary structure not only observed to interact with the
minor groove but also, as seen in Regulatory Factor X1 (RFX1), are able to
contact with major groove (Gajiwala et al. 2000).

Helix-Loop-Helix motif (HLH): Helix-Loop-Helix motif contains two alpha helixes with
different length that connected by a loop. This motif can be dimerized by other
HLH containing proteins with interacting in a coiled-coil arrangement to form
homodimer (binding to the same other) or heterodimer (binding to differ HLH
motif; Nikanta and Angshmman 2015). DNA-binding affinity and specificity are
upgraded by binding dimerization partner (Jones 2004). Since two alpha helixes
rather than one can interact with the target DNA.

Leucine-Zipper motif: Like HLH motif, the structure of
Leucine-Zipper motif is bipartite (Schindler et al. 1992; Wang et al 2015).
Each part of the motif includes a single about 60-amino-acid-long alpha helix
joined together by their ?-helical leucine zipper region (30 amino acid section
at the carboxyl-terminal end of each part) to form short left handed coiled
coil structure like inverted Y-shaped structure (Loscombe et al. 2000). The two-coiled
coil ? helices apart from each other allow their side chains to contact with
the major groove of DNA (Hu et al. 1992). In the zipper region every two turns
of the alpha helix (every eight amino acid positions) contain Leucine or a
similar hydrophobic amino acid that can pack side-by-side with mediated
hydrophobic contacts (Luscombe et al. 2000). Dimerization allows the
juxtaposition of the DNA-binding regions of each subunit alpha helix arms in
Y-shaped structure (amino terminus of each helix) leading to contact with major
groove in opposite direction of the DNA (Pogenberg et al. 2012).

Zinc-Coordinating containing DNA-binding
proteins: Zinc coordinating
DNA binding domains are one of the most predominant motifs in DNA binding
proteins (Rohs et al. 2010). Zinc-coordinating motif consist of about 25-30
amino acids residues containing Cysteine and Histidine amino acids that
coordinate a zinc ion. This motif can coordinate one or more zinc atoms (Ebent
and Altman 2008; Mc-Ewan et al. 2011; Kochauczyk et al. 2015). Proteins
involving Zinc coordinating protein divers overall folding structure and DNA
binding role. Zinc-coordinating residues type and order determine the class of
zinc-coordinating motif (Bagliro 2009). Some important class of zinc
coordinating motif classes is C2H2, C3HC4, C4, C3H, C4HC3 and C2HC5 (where C refers to Cysteine and H
refers to Histidine residues). C2H2 Zinc-coordinating class are the predominant
DNA-binding motif have been identified in transcription factors (Kirishna et
al. 2003). Three-dimensional structures in this motif consist of a two-stranded
anti-parallel ?-sheet and ?- helix; two pairs of conserved histidine and
Cysteine in the alpha helix and second beta sheet coordinate a single zinc ion
(Michalek et al. 2011). The interspersed cysteine and histidine residues
covalently bind zinc atoms, folding the amino acids into loops known as zinc
fingers. Zinc ion (Zn2+) has a structural role in maintaining the protein fold
(Cohen et al. 2002) and affinity to binding to DNA (Mc-Ewan et al. 2011),
however, no role in protein interaction to the DNA. Zinc-coordinating motif
possesses stable structures (Krezel et al. 2014; Pace et al. 2014), and they
rarely undergo conformational changes upon binding their target. The mainly
observed consensus sequence of a single finger is: Cys-
X2-4-Cys-X3-Phe-X3-Leu-X2-His-X3-His (Newton et al. 2000). Zinc-coordinating
motif containing proteins have more than one Zinc-coordinating motif that leads
to making tandem contacts connecting by short oligopeptide, each one specific
for a certain nucleotide sequence in their target DNA molecule and wrap around
the DNA in a spiral manner. The motif binds to three adjacent nucleotides by
inserting alpha helix in the major groove (Krishna et al. 2003). Hormone
receptor proteins can bind to the appropriate ligand and translocation from the
cell cytoplasm to nucleus to bind and regulate transcripted stage(s) containing
one of the important classes of zinc-coordinating motif (Leon et al. 2000;
Kirishna et al. 2003). This class of zinc-coordinating motif is characterized
by two antiparallel alpha helices capped by loops at their amino terminal ends.
The single zinc ion is coordinated in each helix-loop pair by four conserved
cysteine (C4) amino acids (Kirishna et al. 2003). This class of
zinc-coordinating motif interacts with DNA by one of the alpha helixes
contacting in the DNA major groove in the binding site, and the other alpha
helix and loops are contact to the DNA backbone (Luscombe et al. 2000). Also,
the DNA-binding motif can form homo- or heterodimer by the loops leading into
the second alpha helix. Galactose induced gene transcription factor proteins
are one of the zinc-coordinating containing protein that contains two zinc
coordinating ion in each DNA binding domain (Mc-Pherson et al. 2006). This zinc
coordinating motif has a pair of alpha helices that one of them contact with
the DNA major groove in the binding site (Mangeslsdorf and Evans 1995) and the
other makes the backbone interaction. The two Zinc ions are coordinated by six
cysteine amino acids where two cysteine amino acids are shared by both Zinc
ions (Chung et al. 2013). Loop-sheet-helix DNA-binding class of
Zinc-coordinating motif consists of a loop leading out of the main body of the
protein connected to small sheet and an alpha helix. Another loop that leads
back into the protein also draws on the alpha helix. The motif can bind the DNA
major groove and the loop in the minor groove in DNA binding site (Joerger et
al. 2007). However, binding to minor groove are not confer specificity (Luscombe
et al. 2000). The zinc ion is coordinated by three cysteine residues and a
histidine residue in the two loop regions (Luscombe et al. 2000). This motif is
characterized in the DNA binding motif of P53 transcription activator protein (Joeger
et al. 2005; Modhumalav et al. 2009).

Beta sheet mediated DNA interacting motifs: Beta sheet mediated DNA interacting
motifs use beta-stand structure recognition and binding to DNA-binding site, although
less common than alpha helix containing motifs. From this group of DNA-binding
motifs, TATA box binding protein family characterized by using the large beta
sheet in recognition DNA sequence and binding to minor groove in the binding
site (Patikoglou et al. 1999). For binding the ten-stranded antiparallel beta
sheet to minor groove, the DNA in binding site undergoes some conformation and
configuration like unwinding and bending that makes possible contact between
the protein and the binding site minor groove (Lebrun et al. 1997). Also,
smaller two- or three stranded beta sheets or hairpin motifs were observed in
beta sheet mediated DNA interacting motifs to bind either the DNA major or
minor groove (). The proteins with this class of beta sheet containing DNA
interacting motif, such as MetJ repressor, Arc repressor and T-domain families,
are very diverse function. Although the overall structures of these proteins
are different there are common themes in the use of the binding motif (Luscombe
et al. 2000).

Loop mediated DNA interacting motifs: In Loop mediated DNA interacting motifs,
DNA recognition and binding is done by intervening loops (Rohs et al. 2010;
Luscombe et al. 2000). The loop mediated DNA interacting motif containing
proteins are significantly diverse structure outside of the DNA-binding motif.
Immunoglobulin-like loop mediated DNA interacting domain are one of the common
structural domains in transcription factor families like NFkB, STAT p53, RUNX
and TBX families participating in various processes such as immunity, cell
cycle and apoptosis, and development and pattern formation. Structure of Immunoglobulin-like
domain consist of four beta-strands embedded in an antiparallel curled
beta-sheet sandwich with a total of three to five additional strands and binds
DNA in the major groove (Kuriyan et al. 1995; Rohs et al. 2010;
Pourhassan-Moghaddam et al. 2013).