The bZIP domain has a long pair of identical helices, which coil gently around one another in a left-
handed sense. This creates a dimer interface known as a leucine zipperbecause leucines from each of the
-helices intermesh along a line of contact that is co-axial with the long axis of the helical pair. These
amino acids are like protruding knobs on each -helix that fit into complementary hydrophobic pockets on
the partner helix. Such favourable ‘knobs-into-holes’ hydrophobic interactions hold the two parts together
like a zipper. Because the -helix has 3.6 amino acids in a helical turn, the leucines form a left-handed
spiral on the surface of the -helix. Consequently, the hydrophobic regions of those two helices match and
maintain perfect register if the helices coil around one another in a gentle left-handed supercoil. This pack-
ing was deduced by Francis Crick from geometric principles more than 50 years ago.
There are many structural variations of the zipper. For instance, the zipper architecture is elaborated in
the basic helix-loop-helix proteins, as represented by the developmental controlling factor Max. The dimer-
ization interface of the zipper proteins can support homodimers and heterodimers and thus tune their bind-
ing affinity and specificity, and hence their repertoire for genetic regulation. Zipper transcription factors
appear to occur exclusively in eukaryotes, and they are widely distributed within this taxonomic domain and
are found in yeast, plants, insects and vertebrates. In multi-cellular organisms they often play roles in tissue-
specific gene regulation.
10.3.3 Zinc-Bearing Motifs
Collectively, the zinc-bearing transcription factors form the largest group of DNA-binding proteins in the
eukaryotes. Their abundance may be due to their simple, structurally economic folds, which are supported
by metal binding. Further, their modularity may have allowed them to be shuffled and combined readily
in the course of evolution to generate new proteins with different specificity and function.
10.3.3.1 The b–b–aZinc Fingers. The first of the zinc-bearing DNA-binding motifs to be dis-
covered were the ‘zinc fingers’. Transcription factors containing the zinc finger motif are found in a wide
range of eukaryotic organisms, where they play a number of different genetic regulatory roles. In the
human genome, roughly 3% of the genes that encode proteins specify zinc fingers.
The canonical structure of the zinc finger is composed of a peptide loop containing a two-stranded
-hairpin and an -helix. The fold is stabilized by a hydrophobic core and coordination of Zn^2 via
the sulfur atoms of two cysteines and the imidazole nitrogen atoms of two histidines.^11 The inclination of
the helices of the fingers in the transcription factor known as ‘Zif268’ allows stacking of side chains of the
helix and loop regions, which are aligned to interact with the bases in the DNA major groove.^12 The
modular finger structure permits the protein to track along the groove – mainly to one side of it – and to
follow the helical trajectory.
10.3.3.2 The Steroid and Nuclear Receptors. Organisms as diverse as insects and vertebrates have
transcription factors that are activated by small, hydrophobic signalling ligands, such as hormones. These
proteins, known as the steroid and nuclear receptors, use one structural domain to recognize the
signalling ligand and a second domain to recognize specific DNA sequences in the vicinity of the target
gene. Representative examples are the receptors for estrogens, mineralocorticoids, progesterone, gluco-
corticoids and vitamin D (Figures 10.2c). Also in this class are the ‘orphan’ receptors which have no
known ligand.
In these receptor proteins, the DNA-binding domain contains eight cysteines that form two peptide loops
that each cap amphipathic -helices. There is an imperfect structural repeat of the zinc-loop--helix, but
these repeating units do not form independent finger-like structures. Instead, they associate through hydropho-
bic interaction of the two amphipathic -helices to form a globular domain. The -helix exposed by the
amino-terminal module rests in the major groove of the DNA target, for example in the glucocorticoid
receptor, where it directs base contacts. These receptors often bind to DNA as homo- or hetero-dimers and
recognise the spacing between adjacent sites through protein–protein interactions (Section 10.4.6).
Protein–Nucleic Acid Interactions 393