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Nucleic Acids Research Pages 3001-3005  

Binding of the modified daunorubicin WP401 adjacent to a T-G base pair induces the reverse Watson-Crick conformation: crystal structures of the WP401-TGGCCG and WP401-CGG[br5C]CG complexes
Introduction
Materials And Methods
Results And Discussion
   Molecular structure of the two complexes
   The T-G mismatched base pairs adopt a reverse Watson-Crick conformation
   Crystal packing
Conclusion
Acknowledgements
References

Binding of the modified daunorubicin WP401 adjacent to a T-G base pair induces the reverse Watson-Crick conformation: crystal structures of the WP401-TGGCCG and WP401-CGG[br<sup>5</sup>C]CG complexes

Binding of the modified daunorubicin WP401 adjacent to a T-G base pair induces the reverse Watson-Crick conformation: crystal structures of the WP401-TGGCCG and WP401-CGG[br5C]CG complexes

Ratna Dutta, Yi-gui Gao, Waldemar Priebe1, Andrew H.-J. Wang*

Department of Cell and Structural Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA and 1Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77005, USA

Received February 6, 1998; Revised and Accepted April 22, 1998

ABSTRACT

2[prime]-Bromo-4[prime]-epi-daunorubicin ([alpha]-manno configuration, denoted WP401) is a new anthracycline drug that exhibits promising activity toward multidrug-resistant cancer cells. We carried out X-ray diffraction analyses of the complexes formed in the presence of formaldehyde between WP401 and two DNA hexamers, TGGCCG and CGG[br5C]CG. The two complexes crystallized in different crystal lattices with respective crystal data of space group P4322, a = b = 37.20 Å, c = 70.53 Å and space group P43212, a = b = 37.23 Å, c = 61.96 Å. These new crystal forms are different from the P41212 form of other daunorubicin/doxorubicin complexes studied previously. The refined crystal structures at ~2.0 Å resolution revealed that the entire 2:1 drug-DNA complex is in the asymmetrical unit. Two WP401 drug molecules bind to the duplex, with the aglycones intercalated between the CpG or TpG steps and their modified daunosamines in the minor groove. As observed earlier, in the presence of formaldehyde, WP401 more readily forms a covalent adduct with (C/T)GG*:CCG than with (C/T)GC:G*CG (G* is the crosslink site), the opposite of what is seen for daunorubicin and doxorubicin. Surprisingly, the two T-G mismatched base pairs in the WP401-TGGCCG complex adopt the reverse Watson-Crick conformation, instead of the wobble conformation. The unusual T-G reverse Watson-Crick conformation may be required in order to maintain favorable stacking interactions between the base pair and the aglycone of WP401. Our results show that chemical modifications like bromo or iodo substitution on anthracycline drugs have significant effects on their DNA binding properties.

INTRODUCTION

The anthracycline antitumor antibiotics doxorubicin (DOX) and daunorubicin (DNR) (Fig. 1) are important clinical anticancer drugs (1-3). However, as with many other anticancer drugs, they suffer the problems of cardiotoxicity and drug resistance of cancer cells (3). The interactions between the drugs and P glycoprotein, which mediates multidrug resistance (MDR), have been implicated in the latter problem. Extensive studies of derivatives of DOX and DNR suggest that the antitumor (e.g. topoisomerase II-mediated DNA fragmentation) and MDR activities of anthracyclinecompounds may be partitioned into different areas of the molecular framework. In particular, the aglycone ring is required for binding to DNA via intercalation and the sugar moiety may be important for binding to P glycoprotein (4,5).

Recent synthetic efforts have been devoted to new compounds that have enhanced antitumor activities but reduced binding affinity for P glycoprotein (6). That work has revealed an interesting new class of synthetic DNR derivatives having bulky groups at the C2[prime] or the C4[prime] positions of daunosamine that displayed encouraging desirable pharmacological properties. For example, new anthracyclines with a bromine atom at the C2[prime] position of 4[prime]-epi-daunorubicin, named WP400 and WP401, have been synthesized and their biological activities tested. Interestingly, WP401 is active, whereas WP400 is not (6).

We have recently shown that the bulky modification at the C2[prime] position in WP401 alters the sequence preference for the formaldehyde-mediated crosslinking reaction between drug and DNA (7). Formaldehyde normally crosslinks DNR/DOX to a sequence like CGC:G*CG, with the linkage between the N3[prime] amino group of the drug and the N2 amino group of the G* base (8,9). Interestingly, WP401 appears to favor a 5[prime]-CGG*:CCG sequence over the 5[prime]-CGC:GCG* sequence in such reactions (7). The relevance of the formaldehyde-mediated crosslinking reaction between DNR/DOX and DNA has recently been demonstrated (10) and reinforced (11-13).


Figure 1. Molecular formula of 2[prime]-bromo-4[prime]-epi-daunorubicin (WP401) with the bromine atom in the [alpha]-manno and [alpha]-gluco configurations.

Another interesting issue is related to the interactions of drugs with non-canonical DNA structures. For example, bulged DNA structures are often associated with important regions of the genome, such as the origin of replication (14). It is possible that the properties of bulged DNA structure may be modulated by the binding of ligands such as DNA binding anticancer drugs. Some recent examples include the binding of neocarzistatin, which seems to stabilize the bulged structure (15). We have also shown that binding of nogalamycin to two bulged T-containing DNA heptamers, CTbGTACG and CGTACTbG, forced the formation of non-canonical base pairs, the wobble Tb:G and C:Tb base pairs, next to the aglycone ring of the intercalated drug (16). Therefore, binding of an anticancer drug to non-canonical DNA structures may result in stabilization of novel DNA conformations.

Here, we study by X-ray crystallography the structures of WP401 crosslinked via formaldehyde with the DNA hexamer oligonucleotide TGGCCG, consisting of two T:G reverse Watson-Crick base pairs in the duplex structure, and compare them with that of the normal Watson-Crick duplex of CGG[br5C]CG complexed with WP401 (Fig. 2) and other anthracycline-DNA complexes in order to shed some light on the properties of those drugs.

MATERIALS AND METHODS

Oligonucleotides TGGCCG and CGG[br5C]CG were synthesized on a DNA synthesizer and purified by Sepharose G50 column chromatography. WP401 was prepared according to the procedure of Priebe (6). Crystals of 2:1 complexes of WP401 with TGGCCG and CGG[br5C]CG were obtained from a mixture containing 1.2 mM DNA hexamer (single strand), 4 mM BaCl2, 30 mM sodium cacodylate (pH 6.0), 2.5 mM spermine, 1.2 mM drug, and 5% (v/v) 2-methyl-2,4-pentanediol (2-MPD). The solution was equilibrated with 30 ml 40% 2-MPD at room temperature (~25°C) by vapor diffusion according to the procedure of Wang and Gao (17). Orange-red crystals in the form of tetragonal rods appeared after 3-7 days. For the WP401-CGG[br5C]CG complex, the crystal data were as follows: tetragonal space group P43212, a = b = 37.23 Å, c = 61.96 Å, data collection to 2.0 Å resolution at 20°C, unique reflections [>2 [sigma](F0)] 3077, Rsym = 0.060. For the WP401-TGGCCG complex, the crystal data were as follows: tetragonal space group P4322, a = b = 37.20 Å, c = 70.53 Å, data collection to 2.1 Å resolution at -150°C, unique reflections [>2 [sigma](F0)] 2781, Rsym = 0.056. Data were collected on a Rigaku R-Axis IIc image plate area detector system using CuK[alpha] radiation and then processed with the MSC program to obtain the structure factor amplitudes.


Figure 2. The (2F0 - Fc) electron density maps (contoured at the 1.0[sigma] level) of the three base pairs. (A) The G3:br5C10 base pair in the WP401-CGG[br5C]CG formaldehyde-crosslinked complex. The methylene bridge between the G3 N2 amino group and the N3[prime] amino group of daunorubicin can be seen. (B) The T1-G12 base pair in the reverse Watson-Crick conformation of the WP401-TGGCCG complex. G12 is in the syn conformation. (C) The T6-G7 base pair in the reverse Watson-Crick conformation of the WP401-TGGCCG complex.

The two new complexes had different space groups and unit cell dimensions from those of the WP401-CGGCCG complex (7). In the two new crystals, the entire duplex complex is in the asymmetrical unit. Their structures were solved by the molecular replacement method using the X-PLOR package (18). The atomic coordinates from the WP401-CGGCCG complex (7) were used as the starting model for the molecular replacement search. Patterson maps indicated that the base pair stacking direction is along the diagonal of the a-b plane (~52 Å) in both crystals. The structures were refined by the simulated annealing refinement procedure as described in X-PLOR (18). The force field parameters for standard DNA nucleotides were taken from Parkinson et al. (19) as implemented for X-PLOR. Those for WP401 were obtained from comparison with related structures in the Cambridge Crystal Database. Water molecules were then located from subsequent Fourier (2¦F0¦ - ¦Fc¦) maps and added to the refinement using the procedure implemented in the CCP4 suite (20).


Figure 3. Stereoscopic van der Waals drawing of the 2:1 WP401-TGGCCG complex displayed by the program MIDAS (26). The view is into the minor groove, where the two bromo-daunosamines are located. The bulky bromine atoms (red spheres) are in close contact with the C5[prime] positions of the G6/G12 nucleotides. Near the bottom of the figure, the elongated aglycone can be seen protruding toward the right into the major groove.

The two structures were refined to final R factors of 18.9 and 24.5%, with root mean square deviations in bond distances/angles of 0.006 Å/0.91° and 0.009 Å/0.96° from the ideal values, respectively, for the WP401-CGG[br5C]CG and WP401-TGGCCG complexes. In the WP401-TGGCCG complex the 2[prime]-bromo-daunosamine of one of the two independent WP401 is not crosslinked and it appeared to be disordered in two conformations, which might account for the higher R factor. There were 34 and 26 water molecules included in the final refinement for the two respective structures. The respective Rfree values (using 5% data) were 0.242 and 0.318. No ions (Na+, Ba2+ or spermine) could be identified unambiguously. The final atomic coordinates of the structures have been deposited in the Nucleic Acids Database (accession codes DDFB76 for WP401-CGG[br5C]CG and DDFO77 for WP401-TGGCCG). For discussion of the structures below, nucleotides are numbered from C1 (or T1) to G6 in one strand and C7 (or T7) to G12 in the other strand and the two WP401 molecules are numbered D13 and D14.

RESULTS AND DISCUSSION

Molecular structure of the two complexes


Figure 4. Stereoscopic skeletal drawing of the interactions between drug and base in the three WP401-DNA hexamer duplexes viewed from the minor groove. The 5[prime]-C1-G2-G3 (or 5[prime]-T1-G2-G3) strand is on the right and the 5[prime]-C10-C11-G12 strand is on the left. The drug molecules (thick bonds) are intercalated between the terminal two CpG (or TpG) base pairs of the duplex (thin bonds). The bromine atom of WP401 is marked with a large black circle. (A) The 5[prime]-C1-G2-G3:5[prime]-C10-C11-G12 part of the WP401-CGG[br5C]CG formaldehyde-crosslinked complex. (B) The 5[prime]-T1-G2-G3:5[prime]-C10-C11-G12 part of the WP401-TGGCCG complex. In this part, the daunosamine is not crosslinked to DNA and the daunosamine is likely disordered in two different orientations. (C) The 5[prime]-T7-G8-G9:5[prime]-C4-C5-G6 part of the same complex, which is crosslinked.

The overall structures of the two complexes (with the WP401-TGGCCG complex shown in Fig. 3) are similar to other complexes of DNR/DOX drugs with DNA hexamers (7,8,21) in which two drug molecules are intercalated in two CpG (or TpG) steps of the hexamer B-DNA duplex. The aglycone chromophore lies in the DNA double helix with ring D protruding into the major groove and the daunosamine occupying nearly the entire minor groove. The bromine atom at the C2[prime] position is in contact with the DNA backbone but does not inhibit binding of WP401 to DNA. However, when these structures are examined in detail, interesting differences emerge.

The detailed interactions between the WP401 drug and DNA are shown in the close-up views of two WP401-DNA complexes (Fig. 4). For the WP401-CGG[br5C]CG complex, the structure (Fig. 4A) is essentially the same as that of the WP401-CGGCCG complex (7), despite different crystal packing (vide infra). The root mean square deviation between the WP401-CGG[br5C]CG and WP401-CGGCCG complexes (using common atoms) is 0.32 Å. In those complexes, all DNA sugar puckers remain in the S-type family (pseudorotation angle P ranging from 134 to 197°).

The glycosyl [chi] torsion angles of the nucleotides surrounding the drug adopt a similar high anti conformation ([chi] [ap] 270°), except for C1 and C7, which are near -210°. These [chi] angles combined with other changes in the backbone, in particular [zeta], produce the extended conformation to accommodate the large anthracycline drug. As before, the intercalation of anthracycline causes a small helix unwinding (less than -10° per drug). The large buckles of the base pairs above and below the intercalator are again observed, as in other anthracycline-DNA complexes (7,8).


Figure 5. Stereoscopic skeletal drawing of the stacking interactions between the anthracycline drugs (shaded) and two base pairs (thick bonds for the top base pairs), viewed perpendicular to the aglycone chromophore. The 5[prime]-C1-G2 (or 5[prime]-T1-G2) strand is on the right and the 5[prime]-C11-G12 strand is on the left. (A) The 5[prime]-C1-G2 step of the WP401-CGG[br5C]CG complex. (B) The 5[prime]-T1-G2 step of the WP401-TGGCCG complex. (C) The 5[prime]-T7-G8 step of the same complex.

The intercalation of the aglycone is further shown in Figure 5A. The O9 hydroxyl of WP401 forms two hydrogen bonds to N3 (2.71 Å) and N2 (3.00 Å) of the G2 residue, anchoring the drug to DNA. As noted earlier (7), because the bulky bromine atom is close to C5[prime] of the G6 residue, the conformation between the daunosamine and the aglycone in these complexes changed somewhat from what was observed in DNR-DNA complexes (Fig. 6). The C7-O7-C1[prime]-O5[prime] and C7-O7-C1[prime]-C2[prime] torsion angles in the WP401-CGG[br5C]CG complex averaged -81.6 and 158.3°, whereas in DNR-CGCGCG they are -89.5 and 147.6° respectively. The result of these altered torsion angles around the O7-C1[prime] bond is that in WP401-CGGCCG, the N3[prime] amino group is now close to N2 of the G3 residue, an excellent juxtaposition for crosslinking by formaldehyde. In contrast, unmodified DNR can be easily crosslinked to CGCGCG in the presence of formaldehyde (8).


Figure 6. An enlarged view of the superimposition of three anthracycline drugs in two different drug-DNA complexes, WP401-CGG[br5C]CG (dashed line) and WP401-TGGCCG (thin line for D13 and thick line for D14). They are superimposed by a least squares fitting of all common atoms. The three conformations are related by rotating around the O7-C1[prime] glycosyl bond.

Consequently, the bulky C2[prime] bromine atom of WP401 alters the sequence specificity of the formaldehyde-induced crosslinking reaction of the drugs. In the case of WP401, the preferred sequence is 5[prime]-XGG* (X is either T or C), whereas for DNR/DOX it is 5[prime]-G*CG (G* being the crosslinked site).

The T-G mismatched base pairs adopt a reverse Watson-Crick conformation

The structure of the WP401-TGGCCG complex afforded us an opportunity to investigate the influence of mismatched base pairs in DNA on the binding of intercalator drugs. The detailed interactions between WP401 and TGGCCG for the two independent halves of the complex are shown in Figure 4B and C. While at first glance they are similar to those from the WP401-CGG[br5C]CG and WP401-CGGCCG complexes (7), there are significant differences among them. The two T-G mismatched base pairs adopt a reverse Watson-Crick conformation (Fig. 2B and C), instead of the wobble base pairs as might be expected. The G6 and G12 nucleotides are in the syn conformation.

To form a reverse Watson-Crick base pair, the two glycosyl bonds have to come from opposite directions within the base pair. Normally, this would suggest that the duplex will be in the parallel orientation. Indeed, this is the case in a number of parallel duplexes (22). However, the reverse Watson-Crick T-G base pairs in the present structure are found in the antiparallel duplex. This is accomplished by changing the G6 (and G12) nucleotides to the syn conformation.

Why the two T-G base pairs adopt the reverse Watson-Crick conformation may be gleaned from the stacking interactions between the aglycone and the neighboring base pairs shown in Figure 5B and C. If the T-G base pair were in the wobble conformation (with G in the anti conformation), the guanine base would have to move toward ring A of the aglycone (in the direction of the minor groove). Such a movement of the guanine base has several unfavorable consequences. First, the guanine base would now lie over a hemisaturated ring A, with the C7[prime] and C8[prime] protons underneath the six-membered ring of guanine. Second, shearing of the T-G base pair would further stretch the backbone, which would already be extended due to intercalation. Third, the steric problem between D13 Br2[prime] and H5[prime] of G12 that already exists in the WP401-CGG[br5C]CG complex would be exacerbated if G12 were moved further toward ring A of WP401.

Most of the interactions involving the other side of the aglycone remain in place. These include the hydrogen bonds between the O9 hydroxyl of WP401 and N3 and N2 of the G2 (and G8) residue. In the WP401-TGGCCG complex, the DNA sugar puckers are mostly of the S-type family (pseudorotation angle P ranging from 128° for C5 to 192° for G12), except for C4, for which P = 66°. The glycosyl [chi] torsion angles of the nucleotides surrounding the drug adopt the anti conformation for T1/T7 ([chi] [ap] 213°) and C5/C11 ([chi] [ap] 260°) and the syn conformation for G6 and G12 due to the T-G reverse Watson-Crick conformation.


Figure 7. Crystal packing interactions of the two complexes. (A) The WP401-CGG[br5C]CG complex. (B) The WP401-TGGCCG complex. In both lattices, three duplexes of each complex related by the 2-fold screw axis along the diagonal of the a-b plane are shown to be stacked end-over-end. Those columns of pseudo-continuous helices form successive sheets of drug-DNA complexes and, in turn, the sheets are packed in the c-axis direction.

What might be the biological importance of the reverse Watson-Crick T-G mismatched base pair? It has long been known that thymidine is a mutagen. Treatment of cultured cells with a high concentration of thymidine can result in G-C->A-T transition mutations that occur preferentially at the 3[prime] guanine residue of a run of two or more adjacent guanines (23). The T-G mismatch appears to be important in the mutation process and guanine in certain G-rich sequences seems to be a hotspot for the transversion mutation (23). It is possible that not all T-G base pairs adopt the more commonly observed wobble conformation in DNA; in other words, the conformation of the T-G mismatched base pair may be sequence dependent. It would be of interest to know whether alternative conformation (besides a wobble) exist for T-G base pairs in the biologically relevant B-DNA. Since the reverse Watson-Crick conformation in the present structure is found in the two terminal T-G base pairs, it may be argued that such a conformation can only happen at the end of a helix. Thus we asked whether the reverse Watson-Crick conformation of the T-G base pair can be incorporated in B-DNA. A model of B-DNA in which a reverse Watson-Crick base pair is embedded could be constructed without any steric problems (data not shown). We conclude that a reverse Watson-Crick T-G base pair may form if stabilized by other factors (e.g. proteins or drugs).

Crystal packing

Most of the known DNR/DOX-DNA complexes have been crystallized in the tetragonal lattice of space group P4122 (a = b = ~28 Å and c = ~52 Å), with a few exceptions. It is interesting to note that the present two complexes are crystallized in two different tetragonal lattices (Fig. 7). The WP401-CGG[br5C]CG complex forms the larger tetragonal lattice, whereas the WP401-CGGCCG complex forms the `normal' tetragonal lattice. It is worth mentioning that the WP401-CGGC[br5C]G complex, in which the br5C is located in a different sequence location, also forms the same larger tetragonal lattice as the WP401-CGG[br5C]CG complex (data not shown). It is not clear why these two brominated DNA hexamers form the larger lattices, since the bromine atoms in the DNA-drug complexes would not produce any obvious van der Waals clashes in the `normal' tetragonal lattice packing. The WP401-TGCGCG complex also forms a larger tetragonal lattice, but one that is different from that of the WP401-CGG[br5C]CG complex.

In both lattices, the drug-DNA complexes are stacked end-over-end and the helix axes of those stacked duplexes run parallel to the diagonal of the a-b plane. The length of the a-b diagonal is 52 Å, resulting from two end-over-end stacked hexamer complexes. Note that this distance is the same as the c-axis length of the `normal' tetragonal lattice. Successive columns of the stacked duplexes criss-cross using the 43 screw axis along the c-axis, resulting in layers of duplexes with their axes mutually perpendicular to one another. This type of packing arrangement was also observed in the large tetragonal lattice (space group P41212) of the nogalamycin-TGATCA complex (24). The length of the c-axis depends on where the contact points are between two layers of the duplexes. The c-axis of the WP401-CGG[br5C]CG lattice is 61.96 Å, whereas that of the WP401-TGGCCG lattice is 70.53 Å. Two unique intermolecular hydrogen bonds, G6O2P(x,-y,½-z)-D13O4[prime](x,y,z) and T7O5[prime](x,y,z)-T7O5[prime](-x,y,-z), are found in the WP401-TGGCCG lattice. In contrast, only one unique hydrogen bond, G6O3[prime](x,y,z)-C4O2P(½+x, ½-y,¼-z), is found in the WP401-CGG[br5C]CG lattice. The paucity of intermolecular hydrogen bonds in such types of diagonally packed (in the a-b plane) drug-DNA complexes appears to be associated with the lower diffraction resolution of those crystals in comparison with those from the other tetragonal lattices in which all duplexes are aligned in parallel.

CONCLUSION

Our structural studies augment our earlier observations that a bulky group at the C2[prime] position of DNR strongly influences DNA binding, depending on the configuration of the modification and the size of the modifier (e.g. bromine versus iodine) (7). As observed earlier, in the presence of formaldehyde, WP401 forms a covalent adduct with CGGCCG more readily than with CGCGCG, the opposite of what is seen for DNR and DOX. Our results may thus be useful in helping understand the role of formaldehyde in the crosslinking reaction between DOX and DNA (7-13) and, ultimately, in the search for new generations of anthracycline drugs with lower cardiotoxic side effects and higher activity toward resistant tumors.

Surprisingly, we found that WP401 induces the two T-G mismatched base pairs adjacent to the aglycone ring to adopt the reverse Watson-Crick conformation, instead of the wobble conformation. Our modeling study suggests that such an unusual base pair conformation can be accommodated in B-DNA. It would therefore be of interest to test experimentally whether such an unusual base pair conformation in B-DNA can be detected and whether its formation is sequence dependent. As the first step, we have begun a study of the binding of a novel bis-daunorubicin (WP631) (25) with AATGTACGTT, in which TGTACG is the binding site for WP631. Our results should reveal which conformations the two T-G base pairs in the complex may adopt.

ACKNOWLEDGEMENTS

This work was supported by grants from the American Cancer Society (RPG-94-014-04) to A.H.-J.W. and the NIH (CA-55320) and PRS Research Program, the University of Texas M.D.Anderson Cancer Center to W.P. We thank Dr H.Robinson for assistance.

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*To whom correspondence should be addressed. Tel: +1 217 244 6637; Fax: +1 217 244 3181; Email: ahjwang@uiuc.edu

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