Probing Non-Canonical DNA Structures With Anticancer Drugs
Yang, Xianglei
This item is only available for download by members of the University of Illinois community. Students, faculty, and staff at the U of I may log in with your NetID and password to view the item. If you are trying to access an Illinois-restricted dissertation or thesis, you can request a copy through your library's Inter-Library Loan office or purchase a copy directly from ProQuest.
Permalink
https://hdl.handle.net/2142/85497
Description
Title
Probing Non-Canonical DNA Structures With Anticancer Drugs
Author(s)
Yang, Xianglei
Issue Date
2000
Doctoral Committee Chair(s)
Wang, Andrew H.J.
Department of Study
Biophysics and Computational Biology
Discipline
Biophysics and Computational Biology
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Molecular
Language
eng
Abstract
T:G mismatched base pair is associated with many genetic mutations. Understanding its biological consequences can be aided by studying the structural perturbation of DNA caused by T:G base pair and by specific probing of the mismatch using small molecular ligands. We have shown that AR-1-144, a tri-imidazole minor groove binder, recognizes the CCGG sequence. The 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 then 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. The cooperative and tight binding of an AR-1-144 homo-dimer to GAA CTGGTTC 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 hetero-dimer and the Im-Im-Im/Im-Im-Im homo-dimer bind strongly to the CACGG&barbelow;GTC+GACT&barbelow;CGTG duplex. These results suggest that an Im/Im pair can specifically recognize a single T:G mismatch. Together with other sequence-specific recognition rules, our results may be useful in future design of drugs that can recognize and act on a certain gene sequence specifically.
Use this login method if you
don't
have an
@illinois.edu
email address.
(Oops, I do have one)
IDEALS migrated to a new platform on June 23, 2022. If you created
your account prior to this date, you will have to reset your password
using the forgot-password link below.
