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Crystallographic Characterization of an Exocyclic DNA Adduct: 3,N4-etheno-2′-deoxycytidine in the Dodecamer 5′-CGCGAATTεCGCG-3′


Freisinger, Eva; Fernandes, Andrea; Grollman, Arthur P; Kisker, Caroline (2003). Crystallographic Characterization of an Exocyclic DNA Adduct: 3,N4-etheno-2′-deoxycytidine in the Dodecamer 5′-CGCGAATTεCGCG-3′. Journal of Molecular Biology, 329(4):685-697.

Abstract

Exocyclic DNA adducts are formed from metabolites of chemical carcinogens and have also been detected as endogenous lesions in human DNA. The exocyclic adduct 3,N4-etheno-2′-deoxycytidine (εdC), positioned opposite deoxyguanosine in the B-form duplex of the dodecanucleotide d(CGCGAATTεCGCG), has been crystallographically characterized at 1.8 Å resolution. This self-complementary oligomer crystallizes in space group P3212, containing a single strand in the asymmetric unit. The crystal structure was solved by isomorphous replacement with the corresponding unmodified dodecamer structure. Exposure of both structures to identical crystal packing forces allows a detailed investigation of the influence of the exocyclic base adduct on the overall helical structure and local geometry. Structural changes are limited to the εC:G and adjacent T:A and G:C base-pairs. The standard Watson–Crick base-pairing scheme, retained in the T:A and G:C base-pairs, is blocked by the etheno bridge in the εC:G pair. In its place, a hydrogen bond involving O2 of εC and N1 of G is present. Comparison with an εdC-containing NMR structure confirms the general conformation reported for εC:G, including the hydrogen bonding features. Superposition with the crystal structure of a DNA duplex containing a T:G wobble pair shows similar structural changes imposed by both mismatches. Evaluation of the hydration shell of the duplex with bond valence calculations reveals two sodium ions in the crystal.

Abstract

Exocyclic DNA adducts are formed from metabolites of chemical carcinogens and have also been detected as endogenous lesions in human DNA. The exocyclic adduct 3,N4-etheno-2′-deoxycytidine (εdC), positioned opposite deoxyguanosine in the B-form duplex of the dodecanucleotide d(CGCGAATTεCGCG), has been crystallographically characterized at 1.8 Å resolution. This self-complementary oligomer crystallizes in space group P3212, containing a single strand in the asymmetric unit. The crystal structure was solved by isomorphous replacement with the corresponding unmodified dodecamer structure. Exposure of both structures to identical crystal packing forces allows a detailed investigation of the influence of the exocyclic base adduct on the overall helical structure and local geometry. Structural changes are limited to the εC:G and adjacent T:A and G:C base-pairs. The standard Watson–Crick base-pairing scheme, retained in the T:A and G:C base-pairs, is blocked by the etheno bridge in the εC:G pair. In its place, a hydrogen bond involving O2 of εC and N1 of G is present. Comparison with an εdC-containing NMR structure confirms the general conformation reported for εC:G, including the hydrogen bonding features. Superposition with the crystal structure of a DNA duplex containing a T:G wobble pair shows similar structural changes imposed by both mismatches. Evaluation of the hydration shell of the duplex with bond valence calculations reveals two sodium ions in the crystal.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2003
Deposited On:27 Jun 2012 11:38
Last Modified:05 Apr 2016 15:40
Publisher:Elsevier
ISSN:0022-2836
Publisher DOI:https://doi.org/10.1016/S0022-2836(03)00445-5

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