PDBsum entry 3co3

Go to PDB code: 
dna_rna ligands links
Waters ×16
PDB id:
Name: DNA
Title: X-ray crystal structure of a monofunctional platinum-DNA adduct, cis-{pt(nh3)2(pyridine)}2+ bound to deoxyguanosine in a dodecamer duplex
Structure: 5'- d( Dcp Dcp Dtp Dcp Dtp Dcp Dgp Dtp Dcp Dtp Dcp Dc)-3'. Chain: a. Engineered: yes. 5'- d( Dgp Dgp Dap Dgp Dap Dcp Dgp Dap Dgp Dap Dgp Dg)-3'. Chain: b. Engineered: yes
Source: Synthetic: yes. Synthetic: yes
2.16Å     R-factor:   0.227     R-free:   0.254
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
Key ref:
K.S.Lovejoy et al. (2008). cis-Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospects. Proc Natl Acad Sci U S A, 105, 8902-8907. PubMed id: 18579768 DOI: 10.1073/pnas.0803441105
27-Mar-08     Release date:   10-Jun-08    


DOI no: 10.1073/pnas.0803441105 Proc Natl Acad Sci U S A 105:8902-8907 (2008)
PubMed id: 18579768  
cis-Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospects.
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.
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.
  Selected figure(s)  
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.
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21251871 H.Burger, W.J.Loos, K.Eechoute, J.Verweij, R.H.Mathijssen, and E.A.Wiemer (2011).
Drug transporters of platinum-based anticancer agents and their clinical significance.
  Drug Resist Updat, 14, 22-34.  
21421126 M.Ravera, E.Gabano, M.Sardi, G.Ermondi, G.Caron, M.J.McGlinchey, H.Müller-Bunz, E.Monti, M.B.Gariboldi, and D.Osella (2011).
Synthesis, characterization, structure, molecular modeling studies and biological activity of sterically crowded Pt(II) complexes containing bis(imidazole) ligands.
  J Inorg Biochem, 105, 400-409.  
20803225 P.Ruiz-Sánchez, C.König, S.Ferrari, and R.Alberto (2011).
Vitamin B₁₂ as a carrier for targeted platinum delivery: in vitro cytotoxicity and mechanistic studies.
  J Biol Inorg Chem, 16, 33-44.  
21194368 S.Gupta, G.Burckhardt, and Y.Hagos (2011).
SLC22 transporter family proteins as targets for cytostatic uptake into tumor cells.
  Biol Chem, 392, 117-124.  
21104302 S.Li, Y.Chen, S.Zhang, S.S.More, X.Huang, and K.M.Giacomini (2011).
Role of Organic Cation Transporter 1, OCT1 in the Pharmacokinetics and Toxicity of cis-Diammine(pyridine)chloroplatinum(II) and Oxaliplatin in Mice.
  Pharm Res, 28, 610-625.  
21258737 Z.F.Chen, X.Y.Song, Y.Peng, X.Hong, Y.C.Liu, and H.Liang (2011).
High cytotoxicity of dihalo-substituted 8-quinolinolato-lanthanides.
  Dalton Trans, 40, 1684-1692.  
20333441 A.B.Yongye, M.A.Giulianotti, A.Nefzi, R.A.Houghten, and K.Martínez-Mayorga (2010).
Conformational landscape of platinum(II)-tetraamine complexes: DFT and NBO studies.
  J Comput Aided Mol Des, 24, 225-235.  
21031219 C.Sanchez-Cano, M.Huxley, C.Ducani, A.E.Hamad, M.J.Browning, C.Navarro-Ranninger, A.G.Quiroga, A.Rodger, and M.J.Hannon (2010).
Conjugation of testosterone modifies the interaction of mono-functional cationic platinum(II) complexes with DNA, causing significant alterations to the DNA helix.
  Dalton Trans, 39, 11365-11374.  
20448203 D.Wang, G.Zhu, X.Huang, and S.J.Lippard (2010).
X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct.
  Proc Natl Acad Sci U S A, 107, 9584-9589.
PDB codes: 3m3y 3m4o
20730221 G.Ma, Y.Min, F.Huang, T.Jiang, and Y.Liu (2010).
Thioether binding mediates monofunctional platinum antitumor reagents to trans configuration in DNA interactions.
  Chem Commun (Camb), 46, 6938-6940.  
20067471 H.Burger, A.Zoumaro-Djayoon, A.W.Boersma, J.Helleman, E.M.Berns, R.H.Mathijssen, W.J.Loos, and E.A.Wiemer (2010).
Differential transport of platinum compounds by the human organic cation transporter hOCT2 (hSLC22A2).
  Br J Pharmacol, 159, 898-908.  
20689885 J.Mattsson, O.Zava, A.K.Renfrew, Y.Sei, K.Yamaguchi, P.J.Dyson, and B.Therrien (2010).
Drug delivery of lipophilic pyrenyl derivatives by encapsulation in a water soluble metalla-cage.
  Dalton Trans, 39, 8248-8255.  
20473419 K.Meguellati, M.Spichty, and S.Ladame (2010).
Synthesis, spectroscopic and DNA alkylating properties of malondialdehyde (MDA) bis-imine fluorescent adducts.
  Mol Biosyst, 6, 1694-1699.  
19682435 L.Zerzankova, T.Suchankova, O.Vrana, N.P.Farrell, V.Brabec, and J.Kasparkova (2010).
Conformation and recognition of DNA modified by a new antitumor dinuclear PtII complex resistant to decomposition by sulfur nucleophiles.
  Biochem Pharmacol, 79, 112-121.  
20936244 Y.Min, C.Mao, D.Xu, J.Wang, and Y.Liu (2010).
Gold nanorods for platinum based prodrug delivery.
  Chem Commun (Camb), 46, 8424-8426.  
19082006 A.L.Garner, and K.Koide (2009).
Fluorescent method for platinum detection in buffers and serums for cancer medicine and occupational hazards.
  Chem Commun (Camb), (), 83-85.  
20023892 K.S.Lovejoy, and S.J.Lippard (2009).
Non-traditional platinum compounds for improved accumulation, oral bioavailability, and tumor targeting.
  Dalton Trans, (), 10651-10659.  
19449361 O.Nováková, J.Malina, J.Kaspárková, A.Halámiková, V.Bernard, F.Intini, G.Natile, and V.Brabec (2009).
Energetics, conformation, and recognition of DNA duplexes modified by methylated analogues of [PtCl(dien)]+.
  Chemistry, 15, 6211-6221.  
  20046924 R.C.Todd, and S.J.Lippard (2009).
Inhibition of transcription by platinum antitumor compounds.
  Metallomics, 1, 280-291.  
19351185 W.H.Ang, W.W.Brown, and S.J.Lippard (2009).
Preparation of mammalian expression vectors incorporating site-specifically platinated-DNA lesions.
  Bioconjug Chem, 20, 1058-1063.  
19012390 Z.Ma, J.R.Choudhury, M.W.Wright, C.S.Day, G.Saluta, G.L.Kucera, and U.Bierbach (2008).
A non-cross-linking platinum-acridine agent with potent activity in non-small-cell lung cancer.
  J Med Chem, 51, 7574-7580.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.