Several different nuclear receptor monomers recognize the same consensus DNA sequence: ACTGGA.
However, they bind to different DNA sequences, which are distinguished by the spacing between the half-
sites. These elements are bound by a pair of receptors, the relative orientation of which changes with the half-
site separation. This brings different surfaces into register and thus explains how the proteins discriminate
DNA targets.
Some proteins can undergo secondary, tertiary or quaternary conformational changes upon binding to
DNA, and such changes can result in co-operativity. It has been proposed that the DNA element itself can
act as an allosteric ligandthat induces structural changes in the bound protein, and thereby influences the
composition or conformation of multi-component regulatory complexes.^25 In this way, subtle changes in
sequence can increase the combinatorial repertoire of a limited number of genetic regulatory proteins.
10.4.7 Kinetic and Non-Equilibrium Aspects of DNA Recognition
The high degree of specificity in protein–DNA recognition does not require high-affinity binding. For
instance, most specific protein–DNA complexes are stabilized by the energy corresponding to only a few
hydrogen bonds or the liberation of just a handful of bound water molecules – interactions that could be
lacking in their non-specific complexes. Such weak binding may provide kinetic benefits by permitting
protein–DNA complexes to associate and dissociate on timescales that match other processes in the cell.
In many cases, the association rates may be close to maximal for facilitated diffusion.
Some dimeric DNA-binding proteins, such as the leucine zipper proteins (Section 10.3.2), dissociate
into monomers at a significant rate. Dissociable dimeric and oligomeric proteins might have special kinetic
properties for DNA association. Consider, for example, two alternative pathways that may describe the
assembly of a complex. In one pathway, the dimerization occurs prior to binding the DNA, whilst in the sec-
ond, the dimer forms on the DNA only after sequential binding of the subunits. Since in both cases there is a
Protein–Nucleic Acid Interactions 403
Figure 10.11 A representative example of a ternary complex with a specific DNA target. The TBP–TFIIB–DNA
complex (PDB: 1AKH). The TBP (red) docks into the distorted minor groove. This perspective shows
the recognition helix of TFIIB (pink) docked in the major groove at the recognition site. This binding
helps to define the polarity of transcription initiation. The perspective is into the distorted minor
groove engaged by the TBP (and is perpendicular to the view seen in Figure 10.5 in two axes)