The molecular structure of a 4'-epiadriamycin complex with d(TGATCA) at 1.7A resolution: comparison with the structure of 4'-epiadriamycin d(TGTACA) and d(CGATCG) complexes.

The structure of the complex between d(TGATCA) and the anthracycline 4'-epiadriamycin has been determined by crystallographic methods. The crystals are tetragonal, space group P4(1)2(1)2 with unit cell dimensions of a = 28.01, c = 52.95A. The asymmetric unit consists of one strand of hexanucleotide, one molecule of 4'-epiadriamycin and 34 waters. The R-factor is 20.2% for 1694 reflections with F greater than or equal to 2 sigma F to 1.7A. Two asymmetric units associate to generate a duplex complexed with two drug molecules at the d(TpG) steps of the duplex. The chromophore intercalates between these base pairs with the anthracycline amino-sugar positioned in the minor groove. The double helix is a distorted B-DNA type structure. Our structure determination of d(TGATCA) complexed to 4'-epiadriamycin allows for comparison with the previously reported structures of 4'-epiadriamycin bound to d(TGTACA) and to d(CGATCG). The three complexes are similar in gross features and the intercalation geometry is the same irrespective of whether a d(CpG) or d(TpG) sequence is involved. However, the orientation of the amino-sugar displays a dependence on the sequence adjacent to the intercalation site. The flexibility of this amino-sugar may help explain why this class of antibiotics displays a relative insensitivity to base sequence when they bind to DNA.     

Molecular structure, conformation and interactions of antitumor antibiotic cyanonaphthridinomycin, a covalent binder of DNA

X-ray, NMR and molecular modeling studies on cyanonaphthridinomycin (C22H26N4O5), a DNA binding antibiotic, have been carried out to study the structure, conformation and interactions with DNA. The crystals belong to the space group P21 with the cell dimensions of a = 5.934(1)b = 20.684(4), c = 16.866(3)A, gamma = 90.9 degrees and Z = 4(two molecules/asymmetric unit). The structure was solved by direct methods and difference Fourier methods and refined to an R value of 0.087 for 4061 reflections. The conformation of the molecule is compared with that of naphthridinomycin. There are differences in the orientation of the methoxyl group and the saturated oxazole ring. 1 and 2D NMR studies have been carried out and the dihedral angles obtained from coupling constants have been compared with those obtained from the crystal structure. Molecular mechanics studies were carried out to obtain the energy minimized structure and its comparison with X-ray and NMR results. Molecular modelling studies were performed to propose models for drug-DNA interactions. Both partial intercalation and groove-binding models have been proposed.     

Crystal structure at 1.5-A resolution of d(CGCICICG), an octanucleotide containing inosine, and its comparison with d(CGCG) and d(CGCGCG) structures.

The octadeoxyribonucleotide d(CGCICICG) has been crystallized in space group P(6)5(22) with unit cell dimensions of a = b = 31.0 A and c = 43.7 A, and X-ray diffraction data have been collected to 1.5-A resolution. Precession photographs and the self-Patterson function indicate that 12 base pairs of Z-conformation DNA stack along the c-axis, and the double helices pack in a hexagonal array similar to that seen in other crystals of Z-DNA. The structure has been solved by both Patterson deconvolution and molecular replacement methods and refined in space group P(6)5 to an R factor of 0.225 using 2503 unique reflections greater than 3.0 sigma (F). Comparison of the molecules within the hexagonal lattice with highly refined crystal structures of other Z-DNA reveals only minor conformational differences, most notably in the pucker of the deoxyribose of the purine residues. The DNA has multiple occupancy of C:I and C:G base pairs, and C:I base pairs adopt a conformation similar to that of C:G base pairs.     

Commensurate molecules in isostructural crystals of cholesteryl cis- and trans-9-hexadecenoate

At 295 K, crystals of form I of cholesteryl cis-9-hexadecenoate (palmitoleate) and cholesteryl trans-9-hexadecenoate (palmitelaidate) are difficult to distinguish by X-ray diffraction. Both form monoclinic thin plates, space group P21 with two molecules (C43H74O2) A and B in the asymmetric unit. Unit cell dimensions for cholesteryl palmitelaidate (I) are a = 12.827(4), b = 9.075(4), c = 35.67(1) A, beta = 93.42(3) degrees, very similar to those of the palmitoleate crystals. Other crystals (form II) of the palmitelaidate ester are described. The crystal structure of form I of cholesteryl palmitelaidate has been determined from 3657 reflections (sin theta/lambda less than 0.46 A-1) measured at 295 K using CuK alpha X-radiation and refined to give Rw(F) = 0.095. The molecular packing arrangement is isostructural to that of the previously determined crystal structure of cholesteryl palmitoleate. In both crystals, the fatty acid chains of the A molecules are kinked at the double bond but are nearly straight. The chains of B molecules have more complicated dislocations and are bent. It is remarkable that, neglecting their detailed conformations, corresponding fatty acid chains in the two crystal structures have similar overall shapes, although palmitoleate chains have cis-ethylenic groups and palmitelaidate chains have trans groups.     

Anthracycline binding to DNA. High-resolution structure of d(TGTACA) complexed with 4'-epiadriamycin.

Crystallographic methods have been applied to determine the high-resolution structure of the complex formed between the self-complementary oligonucleotide d(TGTACA) and the anthracycline antibiotic 4'-epiadriamycin. The complex crystallises in the tetragonal system, space group P4(1)2(1)2 with a = 2.802 nm and c = 5.293 nm, and an asymmetric unit consisting of a single DNA strand, one drug molecule and 34 solvent molecules. The refinement converged with an R factor of 0.17 for the 2381 reflections with F greater than or equal to 3 sigma F in the resolution range 0.70-0.14 nm. Two asymmetric units associate such that a distorted B-DNA-type hexanucleotide duplex is formed incorporating two drug molecules that are intercalated at the TpG steps. The amino sugar of 4'-epiadriamycin binds in the minor groove of the duplex and displays different interactions from those observed in previously determined structures. Interactions between the hydrophilic groups of the amino sugar and the oligonucleotide are all mediated by solvent molecules. Ultraviolet melting measurements and comparison with other anthracycline-DNA complexes suggest that these indirect interactions have a powerful stabilising effect on the complex.     

Crystal structure of cadaverine dihydrochloride monohydrate.

The structure of cadaverine dihydrochloride monohydrate has been determined by X-ray crystallography with the following features: NH3+ (CH2)5NH3+.2Cl-.H2O, formula weight 191.1, monoclinic, P2, a = 11.814(2)A, b = 4.517(2)A, c = 20.370(3)A, beta = 106.56 degrees (1): V = 1041.9(2)A3; lambda = 1.541A; mu = 53.41; T = 296 degrees; Z = 4, Dx = 1.218 g.cm-3, R = 0.101 for 1383 observed reflections. The crystal is highly pseudo-symmetric with 2 molecules of cadaverine, 4 chloride ions and 2 partially disordered water molecules present in the asymmetric unit. Though both the cadaverine molecules in the asymmetric unit have an all trans conformation, the carbon backbones are slightly bent. Between the concave surfaces of two bent cadaverine molecules exists water channels all along the short b axis. The water molecules present in the channels are partially disordered.     

The crystal structure of 1,2,3,4,6-penta-O-benzoyl-alpha-D-mannopyranose: observation of C-H...pi interaction as a surrogate to O-H...O interaction of a free sugar

The crystal structure of the title compound was determined by X-ray crystallography. The compound crystallized in the orthorhombic space group P2(1)2(1)2(1) with four molecules in the unit cell with a=9.170(2), b=9.873 (2), c=38.831(8) A. The structure was refined to a R index of 0.041 for 7907 independent reflections. The mannopyranose unit adopts a distorted 4C1 conformation. The structure depicts unique network of C-H...pi interactions, very closely resembling the pattern of O-H...O interactions in free sugars. This intriguing and rare observation points to a notion that the supramolecular organization pertaining to a sugar is in-built in the pyranose ring itself.     

Intercalation of water molecules between nucleic acid bases in the crystal structures of 6-azathymine hemihydrate and 5-amino-2-thiocytosine dihydrochloride dihydrate

The crystal structure of 6-azathymine hemihydrate (6AzTH) exhibits a novel intercalation of water molecules interposed half-way between the modified bases 6.3 to 6.7 A apart. The crystal contains four molecules of 6-azathymine (6AzT) and two water molecules as the independent repeating unit. These two water molecules together with the four bases form two separate water sandwiches. In the crystal structure these sandwiches form two sets of local clusters. The anhydrous crystalline form of 6AzT, on the other hand, is stabilized by base stacking interactions. Both the water molecules in 6AzTH that are involved in sandwich formation have trigonal coordination around them. A reexamination of the crystal structure of 5-amino-2-thiocytosine (5A2TC) revealed that one of the water molecules in this structure also forms a water sandwich and has trigonal coordination whereas the other water molecule with tetrahedral coordination does not form a sandwich. The environment and the characteristics of the intercalated water molecule in these structures suggest a possible role for such water intercalations in the dynamics of DNA. Crystals of 6AzTH are monoclinic, space group P21/n, with unit cell parameters a = 8.861 (1), b = 13.177 (3), c = 20.662 (2) A, beta = 93.35 (1) degrees, and Z = 16. From diffractometer data (2503 reflections, greater than or equal to 3 sigma), the crystal structure was solved and refined to an R of 0.056.     

Visualization of drug-nucleic acid interactions at atomic resolution. VIII. Structures of two ethidium/dinucleoside monophosphate crystalline complexes containing ethidium: cytidylyl(3'-5') guanosine

This paper describes two complexes containing ethidium and the dinucleoside monophosphate, cytidylyl(3'-5')guanosine (CpG). Both crystals are monoclinic, space group P2l, with unit cell dimensions as follows: modification 1: a = 13.64 A, b = 32.16 A, c = 14.93 A, beta = 114.8 degrees and modification 2: a = 13.79 A, b = 31.94 A, c = 15.66 A, beta = 117.5 degrees. Each structure has been solved to atomic resolution and refined by Fourier and least squares methods; the first has been refined to a residual of 0.187 on 1,903 reflections, while the second has been refined to a residual of 0.187 on 1,001 reflections. The asymmetric unit in both structures contains two ethidium molecules and two CpG molecules; the first structure has 30 water molecules (a total of 158 non-hydrogen atoms), while the second structure has 19 water molecules (a total of 147 non-hydrogen atoms). Both structures demonstrate intercalation of ethidium between base-paired CpG dimers. In addition, ethidium molecules stack on either side of the intercalated duplex, being related by a unit cell translation along the a axis. The basic feature of the sugar-phosphate chains accompanying ethidium intercalation in both structures is: C3' endo (3'-5') C2' endo. This mixed sugar-puckering pattern has been observed in all previous studies of ethidium intercalation and is a feature common to other drug-nucleic acid structural studies carried out in our laboratory. We discuss this further in this paper and in the accompanying papers.     

Crystal structure of form II of cholesteryl palmitelaidate at 295 K

Form II for cholesteryl palmitelaidate (trans-9-hexadecenoate) (C43H74O2) is monoclinic P2(1) with a = 12.745(3), b = 9.006(2), c = 18.153(4) A, beta = 96.63 (2) degrees, Z = 2. The X-ray crystal structure of form II has been determined from 2506 reflections of which 2126 gave (F greater than 2 sigma). The data up to sin theta/lambda = 0.44A-1 (Dmin = 1.14 A) were measured with CuK alpha radiation from a sealed tube. These were supplemented up to sin theta/lambda = 0.52 A-1 (Dmin = 0.96 A) by measurements on the same crystal using a rotating anode X-ray source. The electron density was diffuse in the ester chain and the atoms of the cholesteryl tail were found to be disordered. The tail and the chain atoms were refined by restrained least squares methods to give R = 0.087 and Rw = 0.10 for reflections with F greater than 2 sigma. Crystal forms I and II represent two standard structure types already characterized for fatty acid esters of cholesterol. In form II, the ester chain is almost fully extended as is also the case for one of the two independent molecules (A) in form I. In form II, the chains pack loosely together for most of their length. M.s. amplitudes of thermal vibration for the chain C-atoms are almost uniform along the entire chain (approximately 0.25 A2 at 295 K). In form I, the proximal part of the A chain is surrounded by rigid cholesteryl groups. In this region, C-atom m.s. amplitudes are much reduced (approximately 0.10 A2) but they increase to about 0.5 A2 at the distal end of the chain where packing is very loose.     

A novel end-to-end binding of two netropsins to the DNA decamers d(CCCCCIIIII)2, d(CCCBr5CCIIIII)2and d(CBr5CCCCIIIII)2.

Netropsin is bound to the DNA decamer d(CCCCCIIIII)2, the C-4 bromo derivative d(CCCBr5CCIIIII)2and the C-2 bromo derivative d(CBr5CCCCIIIII)2in a novel 2:1 mode. Complexes of the native decamer and the C-4 bromo derivative are isomorphous, space group P1, unit cell dimensions a = 32.56 A (32.66), b = 32.59 A (32.77), c = 37.64 A (37.71), alpha = 86.30 degrees (86.01 degrees), beta = 84.50 degrees (84.37 degrees), gamma = 68.58 degrees (68.90 degrees) with two independent molecules (A and B) in the asymmetric unit (values in parentheses are for the derivative). The C-2 bromo derivative is hexagonal P61, unit cell dimensions a = b = 32.13 A, c = 143.92, gamma = 120 degrees with one molecule in the asymmetric unit. The structures were solved by the molecular replacement method. The novelty of the structures is that there are two netropsins bound end-to-end in the minor groove of each B-DNA decamer which has nearly a complete turn. The netropsins are held by hydrogen bonding interactions to the base atoms and by sandwiching van der Waal's interactions from the sugar-phosphate backbones of the double helix similar to every other drug.DNA complex. Each netropsin molecule spans approximately 5 bp. The netropsins refined with their guanidinium heads facing each other at the center, although an orientational disorder for the netropsins cannot be excluded. The amidinium ends stretch out toward the junctions and bind to the adjacent duplexes in the columns of stacked symmetry-related complexes. Both cationic ends of netropsin are bridged by water molecules in one of the independent molecules (molecule A) of the triclinic structures and also the hexagonal structure to form pseudo-continuous drug.decamer helices.     

Molecular Structure,Conformation and Interactions of Antitumor Antibiotic Cyanonaphthridinomycin,a Covalent Binder of DNA

Abstract

X-ray, NMR and molecular modeling studies on cyanonaphthridinomycin (C₂₂ H₂₆N₄O₅), a DNA binding antibiotic, have been carried out to study the structure, conformation and interactions with DNA. The crystals belong to the space group P₂₁ with the cell dimensions of a = 5.934(1), b = 20.684(4), c = 16.866(3)A γ = 90.9° and Z = 4(two molecules/asymmetric unit). The structure was solved by direct methods and difference Fourier methods and refined to an R value of 0.087 for 4061 reflections. The conformation of the molecule is compared with that of naphthridinomycin. There are differences in the orientation of the methoxyl group and the saturated oxazole ring. 1 and 2D NMR studies have been carried out and the dihedral angles obtained from coupling constants have been compared with those obtained from the crystal structure. Molecular mechanics studies were carried out to obtain the energy minimized structure and its comparison with X-ray and NMR results. Molecular modelling studies were performed to propose models for drug-DNA interactions. Both partial intercalation and groove-binding models have been proposed.     

The crystal structure analysis of d(CGCGAASSCGCG)2, a synthetic DNA dodecamer duplex containing four 4'-thio-2'-deoxythymidine nucleotides.

The crystal structure refinement of the synthetic dodecamer d(CGCGAASSCGCG), where S = 4'-thio-2'-deoxythymidine, has converged at R=0.201 for 2605 reflections with F > 2sigma(F) in the resolution range 8.0-2.4 A for a model consisting of the dodecamer duplex and 66 water molecules. A comparison of its structure with that of the native dodecamer d(CGCGAATTCGCG) has revealed that the major differences between the two structures is a change in the conformation of the sugar-phosphate backbone in the regions at and adjacent to the positions of the modified nucleosides. Examination of the fine structural parameters for each of the structures reveals that the thiosugars adopt a C3'-exo conformation in d(CGCGAASSCGCG), rather than the approximate C1'-exo conformation found for the analogous sugars in the structure of d(CGCGAATTCGCG). The observed differences in structure between the two duplexes may help to explain the enhanced resistance to nuclease digestion of synthetic oligonucleotides containing 4'-thio-2'-deoxynucleotides.     

Conformation of the oleate chains in crystals of cholesteryl oleate at 123 K

At 123 K, crystals of cholesteryl cis-9-octadecenoate (cholesteryl oleate, C45H78O2) are monoclinic, space group P2(1) with unit cell dimensions a = 12.356(2), b = 8.980(3), c = 18.382(2) A, beta = 85.49(2) degrees, and have two molecules in the unit cell. The crystal structure including all H atoms has been determined from 3812 independent X-ray reflections with sin theta/lambda less than 0.61 A-1 and refined to give Rw = 0.08. At 123 K, the crystal structure consists of an antiparallel efficient packing of cholesteryl ring systems to form layers that are very similar to those observed in the room temperature structure. The oleate chains that protrude from these layers have a somewhat different packing arrangement from the room temperature structure because they have undergone a conformational change. At 123 K, the oleate chains are well ordered and are almost fully extended except for a kink at the cis double bond. The oleate chains at 123 K are 1.7 A longer than at 295 K due in part to an uncoiling whereby their helical character is lost. On cooling, there is a substantial change in the unit cell beta-angle from obtuse (93.3 degrees) to acute (85.5 degrees) which involves a shearing motion of 2.5 A between adjacent molecular layers. Cell dimension measurements at 10 temperatures in the range 295 K to 123 K show that much of the change occurs in two narrow ranges centered at 262 K and 215 K.     

苍白秤钩风(Diploclisia Glaucescens)中的木脂素——左旋丁香脂素的晶体结构研究

通过X 射线单晶衍射法测定了标题化合物的晶体结构。结果表明 :晶体属正交晶系 ,P2 12 12 1空间群 ,a =8 6 0 10 (3) ,b =13 0 830 (9) ,c =18 1130 (11) ,V =2 0 38 2 0 (2 0 ) 3 ,Z =4 ,Mr =4 18 4 9,Dx =1 36 9g/cm3 ,λ(MoKα) =0 710 73 ,μ(MoKα) =1 12cm-1,F(0 0 0 ) =888。在 0 <2θ <5 0°范围内共收集了 1988个独立衍射点 ,其中可观测衍射点 196 3个 [Ⅰ≥ 8σ(Ⅰ ) ]。晶体结构用直接法解出 ,经全矩阵最小二乘法修正 ,最终偏离因子Rf=0 0 6 2 ,Rw=0 0 5 5。     

A trigonal form of the idarubicin:d(CGATCG) complex; crystal and molecular structure at 2.0 A resolution.

The X-ray crystal structure of the complex between the anthracycline idarubicin and d(CGATCG) has been solved by molecular replacement and refined to a resolution of 2.0 A. The final R-factor is 0.19 for 3768 reflections with Fo > or = 2 sigma (Fo). The complex crystallizes in the trigonal space group P31 with unit cell parameters a = b = 52.996(4), c = 33.065(2) A, alpha = beta = 90 degree, gamma = 120 degree. The asymmetric unit consists of two duplexes, each one being complexed with two idarubicin drugs intercalated at the CpG steps, one spermine and 160 water molecules. The molecular packing underlines major groove-major groove interactions between neighbouring helices, and an unusually low value of the occupied fraction of the unit cell due to a large solvent channel of approximately 30 A diameter. This is the first trigonal crystal form of a DNA-anthracycline complex. The structure is compared with the previously reported structure of the same complex crystallizing in a tetragonal form. The geometry of both the double helices and the intercalation site are conserved as are the intramolecular interactions despite the different crystal forms.     

Conformational changes of cholesteryl palmitoleate in the crystal structure at low temperature

At 123 K, crystals of cholesteryl cis-9-hexadecenoate (cholesteryl palmitoleate, C45H74O2) are monoclinic, space group P2(1) with cell dimensions a = 12.917(7), b = 8.910(5), c = 34.04(1) A, beta = 94.95(7) degrees [lambda(CuK alpha) = 1.5424 A] having two independent molecules (A and B) per unit cell. The crystal structure has been determined from 6178 reflections with sin theta/lambda less than or equal to 0.56 A-1, of which 3406 gave [F] greater than 3 sigma. Structure refinement by alternating cycles of Fourier syntheses and block diagonal least squares gave R = 0.24 for all reflections, R = 0.13 for reflections [F] greater than 3 sigma. At 123 K, the crystal structure consists of closely packed layers very similar to those at 295 K. However, there are major conformational differences in the layer interface region, which affect the ester chain of molecule B and the C(17) tail of molecule A. Although the electron density is diffuse in this region, the B-chain, which is bent, appears to be ordered at 123 K and has a different conformation from the disordered B-chains at 295 K. The change in the A-tail, which is twisted at 123 K and extended at 295 K, is very similar to that which occurs in two of the molecules when anhydrous cholesterol undergoes phase transition. Measurements of the unit cell dimensions at twelve temperatures (295 K to 123 K) indicate that the major changes in the crystal structure of cholesteryl palmitoleate occur in a 10 K range near 173 K.     

Molecular structure, stereochemistry and interactions of steffimycin B, and DNA binding anthracycline antibiotic

The crystal and molecular structure of anthracycline antibiotic steffimycin B(C29H32O13) has been determined by X-ray diffraction and the stereochemistry revealed. The orthorhombic crystals belong to space group P2(1)2(1)2(1), with the dimensions; a = 8.253 (2), b = 8.198 (2), c = 40.850 (8) A and Z = 4. Intensity data were collected for 2518 independent reflections. The structure was solved by direct methods and refined to an R value of 0.066 for 1410 reflections. The configuration in ring A is 7R,8S,9S. Ring A adopts half chair conformation, while the sugar ring has the regular chair conformation. The molecule most probably binds to double helical DNA through intercalation and hydrogen bonding.     

Crystal structure and conformation of a highly constrained linear tetrapeptide Boc-Leu-dehydro Phe-Ala-Leu-OCH3.

The conformation of a tetrapeptide containing a dehydro amino acid, delta ZPhe, in its sequence has been determined in the crystalline state using X-ray crystallographic techniques. The tetrapeptide, Boc-Leu-delta ZPhe-Ala-Leu-OCH3, crystallizes in the orthorhombic space group P2(1)2(1)2(1) with four molecules in a unit cell of dimensions a = 11.655(1) A, b = 15.698(6) A and c = 18.651(3) A V = 3414.9 A and Dcalc = 1.12 g/cm-3. The asymmetric unit contains one tetrapeptide molecule, C30H46N4O7, a total of 41 nonhydrogen atoms. The structure was determined using the direct methods program SHELXS86 and refined to an R-factor of 0.049 for 3347 reflections (I3.0(I). The linear tetrapeptide in the crystal exhibits a double bend of the Type III-I, with Leu1 (phi = -54.1 degrees, psi = -34.5 degrees) and delta ZPhe2 (phi = -59.9 degrees, psi = -17.1 degrees) as the corner residues of Type III turn and delta ZPhe2 (phi = -59.9 degrees, psi = -17.1 degrees) and Ala3 (phi = -80.4 degrees, psi = 0.5 degrees) residues occupying the corners of Type I turn, with delta ZPhe as the common residue in the double bend. The turn structures are further stabilized by two intramolecular 4----1 type hydrogen bonds.