The CREB DNA-Binding Domain Complexed to a Specific Site.
The phosphorylated CREB (cAMP response element binding protein) homodimer binds to DNA in many promoter regions and activates transcription. This model shows the structure of CREB at the CRE site of the somatostatin promoter.
The DNA is shown as Sticks, colored CPK. The central eight bp are the symmetric CRE site: T G A C G T C A
CREB is shown as Cartoons. The basic regions that bind in the major grooves of DNA are colored green. The coiled-coil region, involved with dimerization, is colored purple. Leucine side chains in the heptad-repeat are shown as Sticks and labeled.
A hexahydrated Mg2+ ion that occupies a cavity at the border of the basic regions is Spacefill, colored CPK.
- Dimerization Interactions: Most of the dimer interfaces in bZIP and other coiled-coil proteins are hydrophobic. The two contacts highlighted here contribute to the preference of CREB to form homodimers. In each case, the view is down the coiled-coil axis.
- Leucine Zipper Region: Residues 311-336 are shown in a view down the coiled-coil axis from the N-terminus. The backbone is a purple "rope"; the side chains are Sticks, colored CPK; Leu side chains are colored blue and are labeled on one of the chains.
- Gln 321-Asn 322: The buried Asn 322 residue is also found in other bZIP dimer interfaces. However, the addition of Gln 321 in CREB makes heterodimer formation more costly, energetically. The buried H-bond donors and acceptors are all satisfied in this Gln-Asn dipeptide network (Hit "Distances".)
- Glu 312-Tyr 307: This intersubunit interaction is unique to the CREB family of bZIP proteins. Substitution of Phe for Tyr 307 reduces the stability of the dimer. (The H-bonds appear to be "impossibly short"!)
- DNA Interactions: The CREB-DNA interactions on both sides of the symmetric CRE sequence are identical. The protein is shown as Backbone; the DNA is wireframe or Sticks; Mg2+(H2O)6 is small spheres.
- Half-Site View: Nucleotides on one strand (Chain B) of the half-site are labeled.
- Phosphate Contacts: Most of the Lys and Arg contacts are with phosphates on the "labeled strand". Lys 305 contacts a phosphate on the other half-site.
- Base Contacts: The Arg, Asn, and Ser side chains make H-bonds to the edges of bases in the major groove. The two Ala residues have van der Waals interactions with C-5 methyl groups of thymidine bases.
This structure is described in Schumacher MA, Goodman RH, Brennan RG. (2000) "The structure of a CREB bZIP-somatostatin CRE complex reveals the basis for selective dimerization and divalent cation-enhanced DNA binding". J Biol Chem 275: 35242. PubMed Abstract.
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