3CO3

X-Ray Crystal Structure of a Monofunctional Platinum-DNA Adduct, cis-{Pt(NH3)2(pyridine)}2+ Bound to Deoxyguanosine in a Dodecamer Duplex

Summary for 3CO3

• Entry DOI: 10.2210/pdb3co3/pdb
• Descriptor: 5'-D(*DCP*DCP*DTP*DCP*DTP*DCP*DGP*DTP*DCP*DTP*DCP*DC)-3', 5'-D(*DGP*DGP*DAP*DGP*DAP*DCP*DGP*DAP*DGP*DAP*DGP*DG)-3', cis-diammine(pyridine)chloroplatinum(II), ... (4 entities in total)
• Functional Keywords: platinum-dna duplex, cisplatin, monofunctional pt compound, dna
• Total number of polymer chains: 2
• Total formula weight: 7670.48

Authors

Lovejoy, K.S.,Todd, R.C.,Zhang, S.,McCormick, M.S.,D'Aquino, J.A.,Reardon, J.T.,Sancar, A.,Giacomini, K.M.,Lippard, S.J. (deposition date: 2008-03-27, release date: 2008-06-10, Last modification date: 2024-02-21)

Primary citation

Lovejoy, K.S.,Todd, R.C.,Zhang, S.,McCormick, M.S.,D'Aquino, J.A.,Reardon, J.T.,Sancar, A.,Giacomini, K.M.,Lippard, S.J.
cis-Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospects.
Proc.Natl.Acad.Sci.Usa, 105:8902-8907, 2008

PubMed 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.

PubMed: 18579768
DOI: 10.1073/pnas.0803441105

Experimental method

X-RAY DIFFRACTION (2.16 Å)