title: Molecular structure of cyclic diguanylic acid at 1 A resolution of two crystal forms: self-association, interactions with metal ion/planar dyes and modeling studies.
abstract: Cyclic ribodiguanylic acid, c-(GpGp), is the endogenous effector regulator of cellulose synthase. Its three dimensional structure from two different crystal forms (tetragonal and trigonal) has been determined by x-ray diffraction analysis at 1 A resolution. Both structures were solved by direct methods and refined by block-matrix least squares refinement to R-factors of 0.112 (tetragonal) and 0.119 (trigonal). In both crystal forms, two independent c-(GpGp) molecules associate with each other to form a self-intercalated dimer. All four c-(GpGp) molecules have very similar backbone conformation. The riboses are in the C3'-endo pucker with pseudorotation angles ranging from -7.2 degrees to 16.5 degrees and the bases have anti glycosyl chi angles (-175.5 degrees to 179.7 degrees). In the tetragonal form, a hydrated cobalt ion is found to coordinate to two N7 atoms of adjacent guanines, forcing these two guanines to destack with a large dihedral angle (33 degrees). This metal coordination mechanism has been noted previously in other Pt- or Co-GMP complexes and may be relevant to the binding of the anticancer drug cisplatin to a GpG sequence in DNA. A model of the adduct between cisplatin and a d(CAATGGATTG) duplex has been constructed in which the induced bending of the DNA helix at the Pt crosslinking site is 33 degrees, consistent with earlier electrophoretic analyses. Moreover, c-(GpGp) exhibits unusual spectral properties not seen in other cyclic dinucleotides. It interacts with planar organic intercalator molecules in ways similar to double helical DNA. We propose a cage-like model consisting of a tetrameric c-(GpGp) aggregate in which a large cavity (host molecule) is generated to afford a binding site for certain planar intercalators (guests molecules). The aggregate likely uses a hydrogen bonding scheme the same as that found in the G-quartet molecules, e.g., telomere DNA. The conformation of c-(GpGp) also suggests that certain nearest-neighbor intercalators may be synthesized on the basis of its unique molecular framework. Modeling studies have been carried out to test this hypothesis.
authors.affiliation: Division of Biophysics, University of Illinois at Urbana-Champaign 61801.
authors.forename: Y
authors.initials: Y
authors.lastname: Guan
authors.forename: Y G
authors.initials: YG
authors.lastname: Gao
authors.forename: Y C
authors.initials: YC
authors.lastname: Liaw
authors.forename: H
authors.initials: H
authors.lastname: Robinson
authors.forename: A H
authors.initials: AH
authors.lastname: Wang
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D002945:Cisplatin / Q000737:chemistry; D003035:Cobalt / Q000737:chemistry; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000737:chemistry; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010984:Platinum / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet
chemical_list: D018736:DNA Adducts; C057270:cisplatin-DNA adduct; D003035:Cobalt; D010984:Platinum; C062025:bis(3',5')-cyclic diguanylic acid; D004247:DNA; D006152:Cyclic GMP; D002945:Cisplatin