We've left something out here.

• Organisms can't possibly be transcribing and translating their DNA non-stop

• Such activity would require energy resources far beyond what is typically accessible

• Hence, mechanisms must exist for turning transcription and translation on and off

Upstream of each gene is a control region that specifies where RNA polymerase can initiate transcription

Schematic of an E. coli Control Region

• Specific proteins called activators and repressors in prokaryotes and transcription factors in eukaryotes bind to these sites to inhibit or stimulate transcription

  

An example of a repressor:

E. coli trp Repressor Complexed to DNA

• This particular repressor is a dimer; when bound, the two chains are related by a C₂ axis

• Binding occurs by placing protein helices in successive major grooves of the DNA

• Tryptophan (red) must be bound for the repressor to function

One mechanism by which bacteria become drug resistant is the multiple drug transporter, a cell membrane protein that binds to and expels drugs from the cell.

The gene for it is turned on when the activator binds a foreign molecule.

Here's an example from B. subtilis [Nature, 2001, 409, 378]:

Multiple Drug Transporter Activator Bound to Control Region (1exj)

• In this case, the block between the -10 and -35 blocks is 19 base pairs, placing those two regions on opposite sides of the double helix

• Binding of the activator puts a major kink in the helix, bring -10 and -35 to the same side, so they can interact with the RNA polymerase

The activator LEAFY turns on flower development in angiosperms; like the activators above, it acts as a dimer:

LEAFY Bound to the Control Region in A. thaliana (2vy1)

In this case, it has been possible to identify the specific bases that interact with the protein:

T	T	A	C	G	G	A	C	C	A	C
	A	T	G	C	C	T	G	G	T	G

Another type of transcription factor is the "zinc finger". Here is an example from the mouse:

Murine Transcription Factor Complexed to DNA (1aay)

• The protein folds into three zinc (the purple spheres) fingers, which wrap around the DNA, fitting into the major groove.

The replication machinery then binds to the regulating protein to initiate transcription.

In general, most genes in multicellular organisms are positively regulated: that is, they are normally inactive until turned on by transcription factors.