PDBsum entry 1cx3

DNA

PDB id

1cx3

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Contents

			DNA/RNA

			Ligands

					_NF

PDB id:

1cx3

Links

Name:

DNA

Title:

Solution structure of a complex between d(atgcat)2 and the antitumor bisnaphthalimide lu-79553

Structure:

DNA (5'-d( Ap Tp Gp Cp Ap T)-3'). Chain: a, b. Engineered: yes. Other_details: DNA double helix intercalated by lu-79553

Source:

Synthetic: yes

NMR struc:

15 models

Authors:

J.Gallego,B.R.Reid

Key ref:

J.Gallego and B.R.Reid (1999). Solution structure and dynamics of a complex between DNA and the antitumor bisnaphthalimide LU-79553: intercalated ring flipping on the millisecond time scale. Biochemistry, 38, 15104-15115. PubMed id: 10563793 DOI: 10.1021/bi9915869

Date:

27-Aug-99

Release date:

19-Nov-99

	Headers

	References

DNA/RNA chains

		A-T-G-C-A-T 6 bases
		A-T-G-C-A-T 6 bases

DOI no: 10.1021/bi9915869	Biochemistry 38:15104-15115 (1999)
PubMed id: 10563793

Solution structure and dynamics of a complex between DNA and the antitumor bisnaphthalimide LU-79553: intercalated ring flipping on the millisecond time scale.
J.Gallego, B.R.Reid.

ABSTRACT

Using a combination of nuclear magnetic resonance (NMR) spectroscopy experiments and molecular dynamics, we have analyzed the structure and dynamics of a complex between the bisnaphthalimide drug LU-79553 and the DNA duplex d(ATGCAT)(2). LU-79553 is a DNA-binding topoisomerase II inhibitor that is particularly effective against human solid tumors that are refractory to other drugs. We have found that the two naphthalimide chromophores of the drug bisintercalate at the TpG and CpA steps of the DNA hexanucleotide, stacking mainly with the purine G and A bases from opposite strands. The 3, 7-diazanonylene linker lies in the major groove of the DNA molecule, with its two amino groups hydrogen-bonded to the symmetry-related guanine bases. Unexpectedly, we have detected an unprecedented exchange process between two equivalent and intercalated states of the naphthalimide rings in the drug-DNA complex. The interconversion process takes place by rotational ring flipping, has an activation energy of 22 kcal mol(-)(1) for the two rings, and does not affect the aminoalkyl linker region of the drug. The exchange rate is intermediate to fast on the chemical shift time scale at 36 degrees C (1800 s(-)(1)) but slow at 2 degrees C (20 s(-)(1)). We have also observed limited flexibility for the drug linker on the picosecond time scale on the basis of NMR data and a time-averaged restrained molecular dynamics simulation. The implications of the structural and dynamic features of the DNA-LU-79553 complex on the binding specificity and on the antitumor activity of bisnaphthalimide agents are discussed.

Literature references that cite this PDB file's key reference

PubMed id

Reference

20490406

M.Rettig, W.Langel, A.Kamal, and K.Weisz (2010).
NMR structural studies on the covalent DNA binding of a pyrrolobenzodiazepine-naphthalimide conjugate.

Org Biomol Chem, 8, 3179-3187.

PDB code:

2ky7

17645660

S.McMasters, and L.A.Kelly (2007).
Sequence-dependent interactions of cationic naphthalimides and polynucleotides.

Photochem Photobiol, 83, 889-896.

16094469

S.L.Woodhouse, E.J.Ziolkowski, and L.M.Rendina (2005).
Synthesis and anti-cancer activity of dinuclear platinum(II) complexes containing bis(thioalkyl)dicarba-closo-dodecaborane(12) ligands.

Dalton Trans, (), 2827-2829.

15317822

J.Dai, C.Punchihewa, P.Mistry, A.T.Ooi, and D.Yang (2004).
Novel DNA bis-intercalation by MLN944, a potent clinical bisphenazine anticancer drug.

J Biol Chem, 279, 46096-46103.

PDB code:

1x95

15240833

J.Gallego (2004).
Sequence-dependent nucleotide dynamics revealed by intercalated ring rotation in DNA-bisnaphthalimide complexes.

Nucleic Acids Res, 32, 3607-3614.

15155139

W.A.Denny (2004).
Emerging DNA topisomerase inhibitors as anticancer drugs.

Expert Opin Emerg Drugs, 9, 105-133.

14529286

C.Carrasco, A.Joubert, C.Tardy, N.Maestre, M.Cacho, M.F.Braña, and C.Bailly (2003).
DNA sequence recognition by bispyrazinonaphthalimides antitumor agents.

Biochemistry, 42, 11751-11761.

11352724

S.T.Hoehn, H.D.Junker, R.C.Bunt, C.J.Turner, and J.Stubbe (2001).
Solution structure of Co(III)-bleomycin-OOH bound to a phosphoglycolate lesion containing oligonucleotide: implications for bleomycin-induced double-strand DNA cleavage.

Biochemistry, 40, 5894-5905.

PDB codes:

1g5l 1gj2

11358689

V.Guelev, J.Lee, J.Ward, S.Sorey, D.W.Hoffman, and B.L.Iverson (2001).
Peptide bis-intercalator binds DNA via threading mode with sequence specific contacts in the major groove.

Chem Biol, 8, 415-425.

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 code is shown on the right.