The structure of a CREB bZIP•somatostatin CRE complex reveals the basis for selective dimerization and divalent cation-enhanced DNA binding

The cAMP responsive element-binding protein (CREB) is central to second messenger regulated transcription. To elucidate the structural mechanisms of DNA binding and selective dimerization of CREB, we determined to 3.0 Angstrom resolution, the structure of the CREB bZIP, (residues 283-341) bound to a 21-base pair deoxynucleotide that encompasses the canonical 8-base pair somatostatin cAMP response element (SSCRE), The CREB dimer is stabilized in part by ionic interactions from -Arg(314) to Glu(319') and Glu(328) to, Lys(333') as,,well as a hydrogen bond network that links the carboxamide side chains of Gln(322') -Asn(321)-Asn(321')-Gln(322). Critical to family selective dimerization are intersubunit hydrogen bonds between basic-region residue Tyr(307) and leucine zipper residue: Glu(312), which are conserved in all CREB/CREM/ ATF-1: family members. Strikingly, the structure reveals a hexahydrated Mg2+ ion bound in the cavity between the basic region and SSCRE that makes a water-mediated:DNA contact. DNA binding studies demonstrate that Mg2+ ions enhance CREB bZIP:SSCRE binding by more than 25-fold and suggest a possible physiological role for this ion in somatostatin cAMP response element and potentially other CRE-mediated gene expression.