2KTT

Solution Structure of a Covalently Bound Pyrrolo[2,1-c][1,4]benzodiazepine-Benzimidazole Hybrid to a 10mer DNA Duplex

Summary for 2KTT

• Entry DOI: 10.2210/pdb2ktt/pdb
• Descriptor: 5'-D(*AP*AP*CP*AP*AP*TP*TP*GP*TP*T)-3', (11aS)-7-methoxy-8-(3-{4-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]phenoxy}propoxy)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one (2 entities in total)
• Functional Keywords: dna duplex, pyrrolobenzodiazepine, pbd-benzimidazole hybrid, dna-drug complex, dna
• Total number of polymer chains: 2
• Total formula weight: 6682.78

Authors

Rettig, M.,Weingarth, M.,Langel, W.,Kamal, A.,Kumar, P.P.,Weisz, K. (deposition date: 2010-02-08, release date: 2010-03-09, Last modification date: 2024-05-01)

Primary citation

Rettig, M.,Weingarth, M.,Langel, W.,Kamal, A.,Kumar, P.P.,Weisz, K.
Solution structure of a covalently bound pyrrolo[2,1-c][1,4]benzodiazepine-benzimidazole hybrid to a 10mer DNA duplex.
Biochemistry, 48:12223-12232, 2009

PubMed Abstract: A pyrrolo[2,1-c][1,4]benzodiazepine-benzimidazole hybrid (PBD-BIMZ) derived from the tricyclic anticancer PBD antibiotics can covalently bind to a guanine base at its exocyclic 2-amino group in double-helical DNA. Through the formation of stable DNA adducts, these hybrids have previously been shown to have significant anticancer activity in a number of cell lines. Here, the three-dimensional solution structure of the complex formed between the self-complementary DNA decamer 5'-AACAATTGTT-3' and PBD-BIMZ has been investigated by two-dimensional NMR spectroscopy and NOE distance restraint molecular dynamics simulations. Refinements using an explicit solvation model yielded a complex structure that is in good agreement with the NMR structural data. Successful convergence is indicated by an average mutual root-mean-square deviation of <1 A for three final representative structures selected by clustering methods from the molecular dynamics trajectories at 300 K. The ligand binds in an (11S,11aS) configuration to one of the two symmetrically located guanine bases of the duplex and is oriented with its benzimidazole moiety toward the 5'-end of the modified guanine. It is accommodated within the minor groove covering the centrally located 6 bp. Conformational and helical parameters of the DNA adduct are typical of a B-like duplex, and more significant helical distortions by the covalent binding of PBD-BIMZ are mostly confined to the covalent binding site and the junction between complexed and noncomplexed DNA segments. In contrast to the overall well-determined conformation of the bound hybrid, its terminal N-methylpiperazine ring appears to adopt various conformations associated with increased flexibility.

PubMed: 19911838
DOI: 10.1021/bi901655t

Experimental method

SOLUTION NMR