PDBsum entry 3co3

DNA

PDB id: 3co3

Contents

DNA/RNA

Ligands

C7P

Waters ×16

References listed in PDB file

Key reference

Title

Cis-Diammine(pyridine)chloroplatinum(ii), A monofunctional platinum(ii) antitumor agent: uptake, Structure, Function, And prospects.

Authors

K.S.Lovejoy, R.C.Todd, S.Zhang, M.S.Mccormick, J.A.D'Aquino, J.T.Reardon, A.Sancar, K.M.Giacomini, S.J.Lippard.

Ref.

Proc Natl Acad Sci U S A, 2008, 105, 8902-8907. [DOI no: 10.1073/pnas.0803441105]

PubMed id

18579768

Abstract

We have identified unique chemical and biological properties of a cationic monofunctional platinum(II) complex, cis-diammine(pyridine)chloroplatinum(II), cis-[Pt(NH(3))(2)(py)Cl](+) or cDPCP, a coordination compound previously identified to have significant anticancer activity in a mouse tumor model. This compound is an excellent substrate for organic cation transporters 1 and 2, also designated SLC22A1 and SLC22A2, respectively. These transporters are abundantly expressed in human colorectal cancers, where they mediate uptake of oxaliplatin, cis-[Pt(DACH)(oxalate)] (DACH = trans-R,R-1,2-diaminocyclohexane), an FDA-approved first-line therapy for colorectal cancer. Unlike oxaliplatin, however, cDPCP binds DNA monofunctionally, as revealed by an x-ray crystal structure of cis-{Pt(NH(3))(2)(py)}(2+) bound to the N7 atom of a single guanosine residue in a DNA dodecamer duplex. Although the quaternary structure resembles that of B-form DNA, there is a base-pair step to the 5' side of the Pt adduct with abnormally large shift and slide values, features characteristic of cisplatin intrastrand cross-links. cDPCP effectively blocks transcription from DNA templates carrying adducts of the complex, unlike DNA lesions of other monofunctional platinum(II) compounds like {Pt(dien)}(2+). cDPCP-DNA adducts are removed by the nucleotide excision repair apparatus, albeit much less efficiently than bifunctional platinum-DNA intrastrand cross-links. These exceptional characteristics indicate that cDPCP and related complexes merit consideration as therapeutic options for treating colorectal and other cancers bearing appropriate cation transporters.

Figure 1.
Chemical structures of cisplatin, oxaliplatin, and cDPCP.

Figure 3.
X-ray crystal structure of cDPCP-modified DNA. (A) Schematic diagram showing the DNA sequence and location of the platinum adduct for the complex studied by x-ray crystallography. (B) Structure of the cDPCP-damaged DNA duplex, which maintains a linear B-form conformation despite binding of the Pt complex. (C) Close-up view of the monofunctional Pt–dG adduct, with 2F[o]−F[c] maps contoured at 1σ (blue) and 15σ (green), which show significant electron density around the platinum atom. (D) The platinated base pair (blue) overlaid with ideal B-form DNA (gray). Platinum-binding forces the DNA bases out into the major groove.