Positive regulation of the lac operon by CRP. (a), (b) When lactose is absent, the repressor binds the operator, blocking RNA polymerase and preventing transcription of the lac genes. It does not matter whether glucose is present or absent (and thus whether or not CRP-cAMP binds the operon). (c) When lactose is available, the repressor dissociates from the operator. However, if glucose is also available, low cAMP levels prevent CRP-cAMP formation and DNA binding. RNA polymerase may weakly bind the promoter and occasionally initiate transcription, leading to a very low level of lac operon expression. (d) Only when glucose levels are low, causing cAMP levels to rise and CRP-cAMP to bind the operon, and when lactose is present, causing repressor to dissociate, does the polymerase robustly bind and transcription proceed. (Note that cAMP is enlarged for clarity; it is actually much smaller relative to CRP; see Figure 20-7).