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.
Site-specific insertion of 5-(3-aminopropyl)-2'-deoxyuridine (Z3dU) and 7-deaza-dG into the Dickerson-Drew dodecamers 5'-d(C (1)G (2)C (3)G (4)A (5)A (6)T (7)T (8)C (9) Z (10)C (11)G (12))-3'.5'-d(C (13)G (14)C (15)G (16)A (17)A (18)T (19)T (20)C (21) Z (22)C (23)G (24))-3' (named DDD (Z10)) and 5'-d(C (1)G (2)C (3)G (4)A (5)A (6)T (7) X (8)C (9) Z (10)C (11)G (12))-3'.5'-d(C (13)G (14)C (15)G (16)A (17)A (18)T (19) X (20)C (21) Z (22)C (23)G (24))-3' (named DDD (2+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 DDD (2+Z10) duplex reveals that the tethered cations at base pairs A (5).X (20) and X (8).A (17) extend within the major groove in the 3'-direction, toward conserved Mg (2+) binding sites located adjacent to N+2 base pairs C (3).Z (22) and Z (10).C (15). Bridging waters located between the tethered amines and either Z (10) or Z (22) O (6) stabilize the tethered cations and allow interactions with the N + 2 base pairs without DNA bending. Incorporation of 7-deaza-dG into the DDD (2+Z10) duplex weakens but does not eliminate electrostatic interactions between tethered amines and Z (10) O (6) and Z (22) 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.
Wang
Feng
F
Department of Chemistry, Center in Molecular Toxicology, and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37235, USA.
Li
Feng
F
Ganguly
Manjori
M
Marky
Luis A
LA
Gold
Barry
B
Egli
Martin
M
Stone
Michael P
MP
D020029:Base Pairing / Q000187:drug effects*; D001483:Base Sequence; D002151:Calorimetry; D002412:Cations; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D003460:Crystallization; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D003848:Deoxyguanine Nucleotides / Q000737:chemistry / Q000494:pharmacology; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000378:metabolism; D008969:Molecular Sequence Data; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D009692:Nucleic Acid Heteroduplexes / Q000378:metabolism; D055672:Static Electricity; D013816:Thermodynamics; D044366:Transition Temperature / Q000187:drug effects; D014867:Water / Q000737:chemistry*
D002412:Cations; D003432:Cross-Linking Reagents; D003848:Deoxyguanine Nucleotides; D009588:Nitrogen Mustard Compounds; D009692:Nucleic Acid Heteroduplexes; D014867:Water; C065361:2'-deoxy-7-deazaguanosine triphosphate; C053601:5-(3-aminopropyl)-2'-deoxyuridine; D004247:DNA; D003857:Deoxyuridine