Design of sequence-specific DNA binding ligands that use a two-stranded peptide motif for DNA sequence recognition.
The design and DNA binding activity of beta-structure-forming peptides and netropsin-peptide conjugates are reported. It is found that a pair of peptides-S,S'-bis(Lys-Gly-Val-Cys-Val-NH-NH-Dns)-bridged by an S-S bond binds at least 10 times more strongly to poly(dG).poly(dC) than to poly(dA).poly(dT). This peptide can also discriminate between 5'-GpG-3' and 5'-GpC-3' steps in the DNA minor groove. Based on these observations, new synthetic ligands, bis-netropsins, were constructed in which two netropsin-like fragments were attached by means of short linkers to a pair of peptides-Gly-Cys-Gly- or Val-Cys-Val-bridged by S-S bonds. These compounds possess a composite binding specificity: the peptide chains recognize 5'-GpG-3' steps on DNA, whereas the netropsin-like fragments bind preferentially to runs of 4 AT base pairs. Our data indicate that combining the AT-base-pair specific properties of the netropsin-type structure with the 5'-GpG-3'-specific properties of certain oligopeptides offers a new approach to the synthesis of ligands capable of recognizing mixed sequences of AT- and GC-base pairs in the DNA minor groove. These compounds are potential models for DNA-binding domains in proteins which specifically recognize base pair sequences in the minor groove of DNA.
Nikolaev
V A
VA
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
Grokhovsky
S L
SL
Surovaya
A N
AN
Leinsoo
T A
TA
Sidorova NYu
Zasedatelev
A S
AS
Zhuze
A L
AL
Strahan
G A
GA
Shafer
R H
RH
Gursky
G V
GV
D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D001482:Base Composition; D001483:Base Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D003850:Deoxyribonuclease I / Q000378:metabolism; D018900:Dinucleotide Repeats; D004214:Distamycins / Q000378:metabolism; D004220:Disulfides; D015195:Drug Design; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009429:Netropsin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D009690:Nucleic Acid Conformation; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D012091:Repetitive Sequences, Nucleic Acid; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013816:Thermodynamics
D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic; D004214:Distamycins; D004220:Disulfides; D010455:Peptides; C100298:sibiromycin; D009429:Netropsin; C032161:bis-netropsin; C030000:stallimycin; D004247:DNA; D003850:Deoxyribonuclease I; D003545:Cysteine