A bridging water anchors the tethered 5-(3-aminopropyl)-2′- deoxyuridine amine in the DNA major groove proximate to the N+2 C·G base pair: Implications for formation of interstrand 5′-GNC-3′ cross-links by nitrogen mustards

Feng Wang, Feng Li, Manjori Ganguly, Luis A Marky, Barry Gold, Martin Egli, Michael P. Stone

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Site-specific insertion of 5-(3-aminopropyl)-2′-deoxyuridine (Z3dU) and 7-deaza-dG into the Dickerson-Drew dodecamers 5′-d(C1G 2C3G4A5A6T 7T8C9Z10C11G 12)-3′·5′-d(C13G14C 15G16A17A18T19T 20C21Z22C23G24)-3′ (named DDDZ10) and 5′-d(C1G2C 3G4A5A6T7X 8C9Z10C11G12)- 3′·5′-d(C13G14C15G 16A17A18T19X20C 21Z22C23G24)-3′ (named DDD2+Z10) (X = Z3dU; Z = 7-deaza-dG) suggests a mechanism underlying the formation of interstrand N+2 DNA cross-links by nitrogen mustards, e.g., melphalan and mechlorethamine. Analysis of the DDD2+Z10 duplex reveals that the tethered cations at base pairs A5·X 20 and X8·A17 extend within the major groove in the 3′-direction, toward conserved Mg2+ binding sites located adjacent to N+2 base pairs C3·Z22 and Z10·C15. Bridging waters located between the tethered amines and either Z10 or Z22 O6 stabilize the tethered cations and allow interactions with the N + 2 base pairs without DNA bending. Incorporation of 7-deaza-dG into the DDD2+Z10 duplex weakens but does not eliminate electrostatic interactions between tethered amines and Z10 O6 and Z22 O 6. The results suggest a mechanism by which tethered N7-dG aziridinium ions, the active species involved in formation of interstrand 5′-GNC-3′ cross-links by nitrogen mustards, modify the electrostatics of the major groove and position the aziridinium ions proximate to the major groove edge of the N+2 C·G base pair, facilitating interstrand cross-linking.

Original languageEnglish (US)
Pages (from-to)7147-7157
Number of pages11
JournalBiochemistry
Volume47
Issue number27
DOIs
StatePublished - Jul 8 2008

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Mechlorethamine
Anchors
Base Pairing
Amines
Cations
Water
DNA
Static Electricity
Ions
Melphalan
Coulomb interactions
Electrostatics
Binding Sites
5-(3-aminopropyl)-2'-deoxyuridine

ASJC Scopus subject areas

  • Biochemistry

Cite this

A bridging water anchors the tethered 5-(3-aminopropyl)-2′- deoxyuridine amine in the DNA major groove proximate to the N+2 C·G base pair : Implications for formation of interstrand 5′-GNC-3′ cross-links by nitrogen mustards. / Wang, Feng; Li, Feng; Ganguly, Manjori; Marky, Luis A; Gold, Barry; Egli, Martin; Stone, Michael P.

In: Biochemistry, Vol. 47, No. 27, 08.07.2008, p. 7147-7157.

Research output: Contribution to journalArticle

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title = "A bridging water anchors the tethered 5-(3-aminopropyl)-2′- deoxyuridine amine in the DNA major groove proximate to the N+2 C·G base pair: Implications for formation of interstrand 5′-GNC-3′ cross-links by nitrogen mustards",
abstract = "Site-specific insertion of 5-(3-aminopropyl)-2′-deoxyuridine (Z3dU) and 7-deaza-dG into the Dickerson-Drew dodecamers 5′-d(C1G 2C3G4A5A6T 7T8C9Z10C11G 12)-3′·5′-d(C13G14C 15G16A17A18T19T 20C21Z22C23G24)-3′ (named DDDZ10) and 5′-d(C1G2C 3G4A5A6T7X 8C9Z10C11G12)- 3′·5′-d(C13G14C15G 16A17A18T19X20C 21Z22C23G24)-3′ (named DDD2+Z10) (X = Z3dU; Z = 7-deaza-dG) suggests a mechanism underlying the formation of interstrand N+2 DNA cross-links by nitrogen mustards, e.g., melphalan and mechlorethamine. Analysis of the DDD2+Z10 duplex reveals that the tethered cations at base pairs A5·X 20 and X8·A17 extend within the major groove in the 3′-direction, toward conserved Mg2+ binding sites located adjacent to N+2 base pairs C3·Z22 and Z10·C15. Bridging waters located between the tethered amines and either Z10 or Z22 O6 stabilize the tethered cations and allow interactions with the N + 2 base pairs without DNA bending. Incorporation of 7-deaza-dG into the DDD2+Z10 duplex weakens but does not eliminate electrostatic interactions between tethered amines and Z10 O6 and Z22 O 6. The results suggest a mechanism by which tethered N7-dG aziridinium ions, the active species involved in formation of interstrand 5′-GNC-3′ cross-links by nitrogen mustards, modify the electrostatics of the major groove and position the aziridinium ions proximate to the major groove edge of the N+2 C·G base pair, facilitating interstrand cross-linking.",
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T1 - A bridging water anchors the tethered 5-(3-aminopropyl)-2′- deoxyuridine amine in the DNA major groove proximate to the N+2 C·G base pair

T2 - Implications for formation of interstrand 5′-GNC-3′ cross-links by nitrogen mustards

AU - Wang, Feng

AU - Li, Feng

AU - Ganguly, Manjori

AU - Marky, Luis A

AU - Gold, Barry

AU - Egli, Martin

AU - Stone, Michael P.

PY - 2008/7/8

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N2 - Site-specific insertion of 5-(3-aminopropyl)-2′-deoxyuridine (Z3dU) and 7-deaza-dG into the Dickerson-Drew dodecamers 5′-d(C1G 2C3G4A5A6T 7T8C9Z10C11G 12)-3′·5′-d(C13G14C 15G16A17A18T19T 20C21Z22C23G24)-3′ (named DDDZ10) and 5′-d(C1G2C 3G4A5A6T7X 8C9Z10C11G12)- 3′·5′-d(C13G14C15G 16A17A18T19X20C 21Z22C23G24)-3′ (named DDD2+Z10) (X = Z3dU; Z = 7-deaza-dG) suggests a mechanism underlying the formation of interstrand N+2 DNA cross-links by nitrogen mustards, e.g., melphalan and mechlorethamine. Analysis of the DDD2+Z10 duplex reveals that the tethered cations at base pairs A5·X 20 and X8·A17 extend within the major groove in the 3′-direction, toward conserved Mg2+ binding sites located adjacent to N+2 base pairs C3·Z22 and Z10·C15. Bridging waters located between the tethered amines and either Z10 or Z22 O6 stabilize the tethered cations and allow interactions with the N + 2 base pairs without DNA bending. Incorporation of 7-deaza-dG into the DDD2+Z10 duplex weakens but does not eliminate electrostatic interactions between tethered amines and Z10 O6 and Z22 O 6. The results suggest a mechanism by which tethered N7-dG aziridinium ions, the active species involved in formation of interstrand 5′-GNC-3′ cross-links by nitrogen mustards, modify the electrostatics of the major groove and position the aziridinium ions proximate to the major groove edge of the N+2 C·G base pair, facilitating interstrand cross-linking.

AB - Site-specific insertion of 5-(3-aminopropyl)-2′-deoxyuridine (Z3dU) and 7-deaza-dG into the Dickerson-Drew dodecamers 5′-d(C1G 2C3G4A5A6T 7T8C9Z10C11G 12)-3′·5′-d(C13G14C 15G16A17A18T19T 20C21Z22C23G24)-3′ (named DDDZ10) and 5′-d(C1G2C 3G4A5A6T7X 8C9Z10C11G12)- 3′·5′-d(C13G14C15G 16A17A18T19X20C 21Z22C23G24)-3′ (named DDD2+Z10) (X = Z3dU; Z = 7-deaza-dG) suggests a mechanism underlying the formation of interstrand N+2 DNA cross-links by nitrogen mustards, e.g., melphalan and mechlorethamine. Analysis of the DDD2+Z10 duplex reveals that the tethered cations at base pairs A5·X 20 and X8·A17 extend within the major groove in the 3′-direction, toward conserved Mg2+ binding sites located adjacent to N+2 base pairs C3·Z22 and Z10·C15. Bridging waters located between the tethered amines and either Z10 or Z22 O6 stabilize the tethered cations and allow interactions with the N + 2 base pairs without DNA bending. Incorporation of 7-deaza-dG into the DDD2+Z10 duplex weakens but does not eliminate electrostatic interactions between tethered amines and Z10 O6 and Z22 O 6. The results suggest a mechanism by which tethered N7-dG aziridinium ions, the active species involved in formation of interstrand 5′-GNC-3′ cross-links by nitrogen mustards, modify the electrostatics of the major groove and position the aziridinium ions proximate to the major groove edge of the N+2 C·G base pair, facilitating interstrand cross-linking.

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