Structural basis for cAMP-mediated allosteric control of the catabolite activator protein

Nataliya Popovych, Shiou Ru Tzeng, Marco Tonelli, Richard H. Ebright, Charalampos G. Kalodimos

Research output: Contribution to journalArticlepeer-review

182 Scopus citations


The cAMP-mediated allosteric transition in the catabolite activator protein (CAP; also known as the cAMP receptor protein, CRP) is a textbook example of modulation of DNA-binding activity by small-molecule binding. Here we report the structure of CAP in the absence of cAMP, which, together with structures of CAP in the presence of cAMP, defines atomic details of the cAMP-mediated allosteric transition. The structural changes, and their relationship to cAMP binding and DNA binding, are remarkably clear and simple. Binding of cAMP results in a coil-to-helix transition that extends the coiled-coil dimer-ization interface of CAP by 3 turns of helix and concomitantly causes rotation, by ≈ 60°, and translation, by 7 Å, of the DNA-binding domains (DBDs) of CAP, positioning the recognition helices in the DBDs in the correct orientation to interact with DNA. The allosteric transition is stabilized further by expulsion of an aromatic residue from the cAMP-binding pocket upon cAMP binding. The results define the structural mechanisms that underlie allosteric control of this prototypic transcriptional regulatory factor and provide an illustrative example of how effector-mediated structural changes can control the activity of regulatory proteins.

Original languageEnglish (US)
Pages (from-to)6927-6932
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
StatePublished - Apr 28 2009
Externally publishedYes


  • Allosteric regulation
  • Gene regulation
  • NMR structure
  • Protein NMR
  • cAMP binding


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