Crystal structure of the anticancer drug cisplatin bound to duplex DNA

  • Takahara P
  • Frederick C
  • Lippard S
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Abstract

The X-ray crystal structure of d(CCTCTG*G*TCTCC)·d(GGAGACCAGAGG), where G*G* represents the major adduct of the antitumor drug cisplatin on a duplex DNA dodecamer, was solved to a resolution of 2.6 Å (R = 0.203, R-free = 0.245). The molecule crystallizes in the space group P1, with unit cell dimensions a = 31.27 Å, b = 35.46 Å, c = 47.01 Å, α = 79.81°, ? = 84.75°, ? = 82.79°, and Z = 2. Two molecules in the asymmetric unit are related by a local two-fold symmetry axis and have very similar structures. The duplexes are bent significantly, each having a 26° roll toward the major groove at the site of the platinum intrastrand cross-link. The platinum atom binds to the N7 atoms of adjacent guanine residues, compacting the major groove and widening and flattening the minor groove. Because of the shallow roll, the platinum atom is displaced from the planes of the guanine bases by ?1 Å and is considerably strained. The overall structure of the cisplatin-modified duplex contains an unusual juxtaposition of A-like and B-like helical segments. This bent structure is accommodated by an interesting and novel packing arrangement in the crystal. One end of each duplex packs end-to-end with another, as in crystal structures of B-DNA, whereas the other end packs into the minor groove of an adjacent molecule, much like A-DNA crystal packing. An unusual backbone-to-backbone packing interaction involving several CH···O hydrogen bonds was also observed. The widened minor groove and the bend caused by platinum binding resembles the DNA component of the structure of the HMG domains of SRY bound to its recognition site DNA. This similarity suggests how HMG-domain proteins might recognize cisplatin?DNA adducts. The X-ray crystal structure of d(CCTCTG*G*TCTCC)·d(GGAGACCAGAGG), where G*G* represents the major adduct of the antitumor drug cisplatin on a duplex DNA dodecamer, was solved to a resolution of 2.6 Å (R = 0.203, R-free = 0.245). The molecule crystallizes in the space group P1, with unit cell dimensions a = 31.27 Å, b = 35.46 Å, c = 47.01 Å, α = 79.81°, ? = 84.75°, ? = 82.79°, and Z = 2. Two molecules in the asymmetric unit are related by a local two-fold symmetry axis and have very similar structures. The duplexes are bent significantly, each having a 26° roll toward the major groove at the site of the platinum intrastrand cross-link. The platinum atom binds to the N7 atoms of adjacent guanine residues, compacting the major groove and widening and flattening the minor groove. Because of the shallow roll, the platinum atom is displaced from the planes of the guanine bases by ?1 Å and is considerably strained. The overall structure of the cisplatin-modified duplex contains an unusual juxtaposition of A-like and B-like helical segments. This bent structure is accommodated by an interesting and novel packing arrangement in the crystal. One end of each duplex packs end-to-end with another, as in crystal structures of B-DNA, whereas the other end packs into the minor groove of an adjacent molecule, much like A-DNA crystal packing. An unusual backbone-to-backbone packing interaction involving several CH···O hydrogen bonds was also observed. The widened minor groove and the bend caused by platinum binding resembles the DNA component of the structure of the HMG domains of SRY bound to its recognition site DNA. This similarity suggests how HMG-domain proteins might recognize cisplatin?DNA adducts.

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Authors

  • Patricia M. Takahara

  • Christin A. Frederick

  • Stephen J. Lippard

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