Computational studies support the role of the C7-sibirosamine sugar of the pyrrolobenzodiazepine (PBD) sibiromycin in transcription factor inhibition
Jackson, PJ; James, CH; Jenkins, TC; Rahman, KM; Thurston, DE
| HERO ID | 2902556 |
|---|---|
| In Press | No |
| Year | 2014 |
| Title | Computational studies support the role of the C7-sibirosamine sugar of the pyrrolobenzodiazepine (PBD) sibiromycin in transcription factor inhibition |
| Authors | Jackson, PJ; James, CH; Jenkins, TC; Rahman, KM; Thurston, DE |
| Journal | ACS Chemical Biology |
| Volume | 9 |
| Issue | 10 |
| Page Numbers | 2432-2440 |
| Abstract | The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a group of sequence-selective, DNA minor-groove binding agents that covalently attach to guanine residues. Originally derived from Streptomyces species, a number of naturally occurring PBD monomers exist with varying A-Ring and C2-substituents. One such agent, sibiromycin, is unusual in having a glycosyl residue (sibirosamine) at its A-Ring C7-position. It is the most cytotoxic member of the naturally occurring PBD family and has the highest DNA-binding affinity. Recently, the analogue 9-deoxysibiromyin was produced biosynthetically by Yonemoto and co-workers.1 Differing only in the loss of the A-Ring C9-hydroxyl group, it was reported to have a significantly higher DNA-binding affinity than sibiromycin based on DNA thermal denaturation studies, although these data have since been retracted.2 As deletion of the C9-OH moiety, which points toward the DNA minor groove floor, might intuitively be expected to reduce DNA-binding affinity through the loss of hydrogen bonding, we carried out molecular dynamics simulations on the interaction of both molecules with DNA over a 10 ns time-course in explicit solvent. Our results suggest that the two molecules may differ in their sequence-selectivity and that 9-deoxysibiromycin should have a lower binding affinity for certain sequences of DNA compared to sibiromycin. Our molecular dynamics results indicate that the C7-sibirosamine sugar does not form hydrogen bonding interactions with groups in the DNA minor-groove wall as previously reported, but instead points orthogonally out from the minor groove where it may inhibit the approach of DNA control proteins such as transcription factors. This was confirmed through a docking study involving sibiromycin and the GAL4 transcription factor, and these results could explain the significantly enhanced cytotoxicity of sibiromycin compared to other PBD family members without bulky C7-substituents. |
| Doi | 10.1021/cb5002203 |
| Pmid | 25111266 |
| Is Certified Translation | No |
| Dupe Override | No |
| Is Public | Yes |
| Language Text | English |