The molecular origin of DNA-drug specificity in netropsin and distamycin

M. L. Kopka, C. Yoon, D. Goodsell, P. Pjura, R. E. Dickerson

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762 Scopus citations


X-ray analysis of the complex of netropsin with the B-DNA dodecamer of sequence C-G-C-G-A-A-T-T-(Br)C-G-C-G reveals that the antitumor binds within the minor groove by displacing the water molecules of the spine of hydration. Netropsin amide NH furnish hydrogen bonds to bridge DNA adenine N-3 and thymine O-2 atoms occurring on adjacent base pairs and opposite helix strands, exactly as with the spine of hydration. The narrowness of the groove forces the netropsin molecule to sit symmetrically in the center, with its two pyrrole rings slightly non-coplanar so that each ring is parallel to the walls of its respective region of the groove. Drug binding neither unwinds nor elongates the double helix, but it does force open the minor groove by 0.5-2.0 Å, and it bends back the helix axis by 8° across the region of attachment. The neutropsin molecule has an intrinsic twist that favors insertion into the minor groove of B-DNA, and it is given a small additional twist upon binding. The base specificity that makes netropsin bind preferentially to runs of four or more A.T base pairs is provided not by hydrogen bonding but by close van der Waals contacts between adenine C-2 hydrogens and CH groups on the pyrrole rings of the drug molecule. Substitution of one or more pyrroles by imidazole could permit recognition of G.C base pairs as well, and it could lead to a class of synthetic 'lexitropsins', capable of reading any desired short sequence of DNA base pairs.

Original languageEnglish (US)
Pages (from-to)1376-1380
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number5
StatePublished - 1985
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General


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