The primary mode of binding of cisplatin to a B-DNA dodecamer: C-G-C-G-A-A-T-T-C-G-C-G.

Wing, Richard M.; Pjura, Philip; Drew, Horace R.; Dickerson, Richard E.

doi:10.1002/j.1460-2075.1984.tb01951.x

Cited by 92 publications

(68 citation statements)

References 24 publications

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“…Briefly, the same configuration of pol II, DNA, and RNA as found in the structure containing cis-fPtðNH 3 Þ 2 ðpyÞg 2þ was used for these two complexes. The geometry of the fPtðNH 3 Þ 3 g 2þ moiety was taken from a previous structure where it binds to a B-DNA dodecamer (PDB ID: 5BNA) (39). Docking was achieved by aligning the damaged guanosine base of the two structures.…”

Section: Methodsmentioning

confidence: 99%

X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct

Wang

Zhu

Huang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

120

118

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DNA is a major target of anticancer drugs. The resulting adducts interfere with key cellular processes, such as transcription, to trigger downstream events responsible for drug activity. cisDiammine(pyridine)chloroplatinum(II), cDPCP or pyriplatin, is a monofunctional platinum(II) analogue of the widely used anticancer drug cisplatin having significant anticancer properties with a different spectrum of activity. Its novel structure-activity properties hold promise for overcoming drug resistance and improving the spectrum of treatable cancers over those responsive to cisplatin. However, the detailed molecular mechanism by which cells process DNA modified by pyriplatin and related monofunctional complexes is not at all understood. Here we report the structure of a transcribing RNA polymerase II (pol II) complex stalled at a site-specific monofunctional pyriplatin-DNA adduct in the active site. The results reveal a molecular mechanism of pol II transcription inhibition and drug action that is dramatically different from transcription inhibition by cisplatin and UV-induced 1,2-intrastrand cross-links. Our findings provide insight into structure-activity relationships that may apply to the entire family of monofunctional DNA-damaging agents and pave the way for rational improvement of monofunctional platinum anticancer drugs.anticancer | chemotherapy | DNA damage | pyriplatin | transcription T he DNA template for transcription is not only the site of inborn errors of metabolism and of continuous attack by harmful environmental agents, but it also represents a major target for cancer therapy. Platinum-based anticancer drugs such as cisplatin, cis-diamminedichloroplatinum(II), are widely used and among the most effective antineoplastic treatments (1, 2). Platinum-based drugs typically form bifunctional intra-or interstrand DNA cross-links by covalent bonding to the N 7 positions of two guanosine residues, triggering a variety of cellular processes, including transcription inhibition with attendant apoptosis (1, 2). However, resistance and side effects can require withdrawal of these drugs before they can effect a cure in certain types of cancer (3).In the effort to find new compounds that circumvent resistance to conventional bifunctional platinum-based drugs, a class of monofunctional platinum compounds were synthesized and screened for anticancer activity (4-6). In contrast to other inactive monofunctional platinum(II) compounds such as ½PtðdienÞCl þ and ½PtðNH 3 Þ 3 Cl þ , cis-diammine(pyridine)chloroplatinum(II) [cDPCP or "pyriplatin" (Fig. 1)] and related complexes display significant anticancer properties and a different spectrum of activity compared to conventional platinum-based drugs. These features render them attractive candidates for treating cisplatin-refractory patients if the potency could be raised to or beyond the level of that of cisplatin (4, 5, 7). Pyriplatin exhibits unique chemical and biological properties, forming monofunctional DNA adducts ( Fig. 1 and Fig. S1) that can inhibit transcription an...

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Section: Methodsmentioning

confidence: 99%

X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct

Wang

Zhu

Huang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

120

118

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“…This monoadduct has been observed in the X-ray structure of a platinated dodecanucleotide 72). It has been isolated from DNA by two methods and identified by comparison with model compounds of known structure.…”

Section: Platinum-dna Adductsmentioning

confidence: 97%

Metal Antitumor Compounds: The Mechanism of Action of Platinum Complexes

Johnson

Butour

Villani

et al. 1989

Progress in Clinical Biochemistry and Medicine

163

122

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Cisplatin (cis-diamminedichloroplatinum(II») is widely used in the treatment of testicular and ovarian cancers. A number of biological and biochemical results indicate that the reaction of cisplatin with DNA is responsible for the cytotoxic action of this drug. The effect of platinum compounds on the conformation and stability of DNA has been investigated and several platinum-DNA adducts have been identified in vitro and in vivo. Preliminary experiments have quantified the effect of these different lesions on DNA replication, their capacity to induce mutations and their susceptibility to DNA repair processes. Additional DNA damage may be created by platinum(IV) compounds, perhaps during their reduction to platinum(II) compounds by the cell.

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“…On average, the confal score improved by 7 after application of the PDB_REDO protocol, but the fraction of reassigned NtC classes varied widely between 0 and 77% in individual structures. The confal values showed significant improvement, for example, in the structure with PDB entry 1d29 (Larsen et al, 1991), while no changes were observed in PDB entry 4i9v (Szulik et al, 2015) and a mixture of increased and lowered confal values were found in PDB entry 5bna (Wing et al, 1984) (Supplementary Table S3). Overall, the PDB_REDO protocol improves the deposited coordinates somewhat, but better molecular templates provided by the NtC classes can constrain the re-refinement more effectively.…”

Section: B-a: Conformers Bridging B-form To A-formmentioning

confidence: 99%

A DNA structural alphabet provides new insight into DNA flexibility

Schneider

Božíková

Nečasová

et al. 2018

Acta Cryst Sect D Struct Biol

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DNA is a structurally plastic molecule, and its biological function is enabled by adaptation to its binding partners. To identify the DNA structural polymorphisms that are possible in such adaptations, the dinucleotide structures of 60 000 DNA steps from sequentially nonredundant crystal structures were classified and an automated protocol assigning 44 distinct structural (conformational) classes called NtC (for Nucleotide Conformers) was developed. To further facilitate understanding of the DNA structure, the NtC were assembled into the DNA structural alphabet CANA (Conformational Alphabet of Nucleic Acids) and the projection of CANA onto the graphical representation of the molecular structure was proposed. The NtC classification was used to define a validation score called confal, which quantifies the conformity between an analyzed structure and the geometries of NtC. NtC and CANA assignment were applied to analyze the structural properties of typical DNA structures such as Dickerson-Drew dodecamers, guanine quadruplexes and structural models based on fibre diffraction. NtC, CANA and confal assignment, which is accessible at the website https://dnatco.org, allows the quantitative assessment and validation of DNA structures and their subsequent analysis by means of pseudo-sequence alignment. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:Acta_Cryst_D:2.

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The primary mode of binding of cisplatin to a B-DNA dodecamer: C-G-C-G-A-A-T-T-C-G-C-G.

Cited by 92 publications

References 24 publications

X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct

X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct

Metal Antitumor Compounds: The Mechanism of Action of Platinum Complexes

A DNA structural alphabet provides new insight into DNA flexibility

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