The structure of a CREB bZIP center dot 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 mes senger regulated transcription. To elucidate the structural mechanisms of D NA binding and selective dimerization of CREB, we determined to 3.0 Angstro m resolution, the structure of the CREB bZIP, (residues 283-341) bound to a 21-base pair deoxynucleotide that encompasses the canonical 8-base pair so matostatin cAMP response element (SSCRE), The CREB dimer is stabilized in p art 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 c hains of Gln(322') -Asn(321)-Asn(321')-Gln(322). Critical to family selecti ve dimerization are intersubunit hydrogen bonds between basic-region residu e Tyr(307) and leucine zipper residue: Glu(312), which are conserved in all CREB/CREM/ ATF-1: family members. Strikingly, the structure reveals a hexa hydrated Mg2+ ion bound in the cavity between the basic region and SSCRE th at 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 e lement and potentially other CRE-mediated gene expression.