1B0S

BINDING OF AR-1-144, A TRI-IMIDAZOLE DNA MINOR GROOVE BINDER, TO CCGG SEQUENCE ANALYZED BY NMR SPECTROSCOPY

Summary for 1B0S

• Entry DOI: 10.2210/pdb1b0s/pdb
• NMR Information: BMRB: 4392
• Descriptor: DNA (5'-D(*GP*AP*AP*CP*CP*GP*GP*TP*TP*C)-3'), (2-{[4-({4-[(4-FORMYLAMINO-1-METHYL-1H-IMIDAZOLE-2-CARBONYL)-AMINO]-1-METHYL-1H-IMIDAZOLE-2-CARBONYL}-AMINO)-1-METHYL-1 H-IMIDAZOLE-2-CARBONYL]-AMINO}-ETHYL)-DIMETHYL-AMMONIUM (2 entities in total)
• Functional Keywords: anticancer drug, drug design, dna structure, sequence specific recognition, dna
• Total number of polymer chains: 2
• Total formula weight: 7063.03

Authors

Yang, X.-L.,Kaenzig, C.,Lee, M.,Wang, A.H.-J. (deposition date: 1998-11-12, release date: 1999-08-31, Last modification date: 2023-12-27)

Primary citation

Yang, X.L.,Kaenzig, C.,Lee, M.,Wang, A.H.
Binding of AR-1-144, a tri-imidazole DNA minor groove binder, to CCGG sequence analyzed by NMR spectroscopy.
Eur.J.Biochem., 263:646-655, 1999

PubMed Abstract: The interactions of N-[2-(dimethylamino)ethyl]-1-methyl-4-[1-methyl-4-[4-formamido-1-meth ylimidazole-2-carboxamido]imidazole-2-carboxamido]imidazole-2-c arboxa mide (AR-1-144), a tri-imidazole polyamide minor groove binder, with DNA have been investigated by NMR and CD spectroscopy. A series of DNA oligonucleotides with a C/G-containing four-bp core, i.e. CCGG, CGCG, GGCC, and GCGC, have been titrated with AR-1-144 at different ratios. AR-1-144 favors the CCGG sequence. The flanking sequence of the CCGG core also influences the binding preference, with a C or T being favored on the 3'-side of the CCGG core. The three-dimensional structure of the symmetric 2:1 side-by-side complex of AR-1-144 and GAACCGGTTC, determined by NOE-constrained NMR refinement, reveals that each AR-1-144 binds to four base pairs, i.e. at C5-G6-G7-T8, with every amide-imidazole unit forming two potential hydrogen bonds with DNA. The same DNA binding preference of AR-1-144 was also confirmed by circular dichroism spectroscopy, indicating that the DNA binding preference of AR-1-144 is independent of concentration. The cooperative binding of an AR-1-144 homodimer to the (purine)CCGG(pyrimidine) core sequence appears to be weaker than that of the distamycin A homodimer to A/T sequences, most likely due to the diminished hydrophobic interactions between AR-1-144 and DNA. Our results are consistent with previous footprinting data and explain the binding pattern found in the crystal structure of a di-imidazole drug bound to CATGGCCATG.

PubMed: 10469127
DOI: 10.1046/j.1432-1327.1999.00515.x

Experimental method

SOLUTION NMR