Nucleic Acids Research, Vol 27, Issue 21 4183-4190, Copyright © 1999 by Oxford University Press
XL Yang, IV Hubbard RB,, M Lee, ZF Tao, H Sugiyama and AH Wang
The T:G mismatched base pair is associated with many genetic mutations.
Understanding its biological consequences may be aided by studying the
structural perturbation of DNA caused by a T:G base pair and by specific
probing of the mismatch using small molecular ligands. We have shown
previously that AR-1-144, a tri-imidazole (Im-Im-Im) minor groove binder,
recognizes the sequence CCGG. NMR structural analysis of the symmetric 2:1
complex of AR-1-144 and GAACCGGTTC revealed that each AR- 1-144 binds to
four base pairs with the guanine N2 amino group forming a bifurcated
hydrogen bond to a side-by-side Im/Im pair. We predicted that the free G-N2
amino group in a T:G wobble base pair can form two individual hydrogen
bonds to a side-by-side Im/Im pair. Thus an Im/Im pair may be a good
recognition motif for a T:G base pair in DNA. Cooperative and tight binding
of an AR-1-144 homodimer to GAACTGGTTC permits a detailed structural
analysis by 2D NOE NMR refinement and the refined structure confirms our
prediction. Surprisingly, AR-1-144 does not bind to GAATCGGTTC. We further
show that both the Im-Im-Im/Im-Py-Im heterodimer and the Im-Im-Im/Im-Im-Im
homodimer bind strongly to the CACGGGTC + GACTCGTG duplex. These results
together suggest that an Im/Im pair can specifically recognize a single T:G
mismatch. Our results may be useful in future design of molecules (e.g.
linked dimers) that can recognize a single T:G mismatch with specificity.
ARTICLES
Imidazole-imidazole pair as a minor groove recognition motif for T:G mismatched base pairs
Department of Cell and Structural Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
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