Double-stranded DNA minor groove at 5′-PuGATCPy-3′ guanine-containing sequences (PuGATCPy)

The target Double-stranded DNA minor groove at 5′-PuGATCPy-3′ guanine-containing sequences refers to a specific six-base-pair genomic motif (where Pu is a purine and Py is a pyrimidine) that serves as the primary binding site for pyrrolobenzodiazepine (PBD) dimers. These compounds are potent DNA-cross-linking agents that fit precisely into the minor groove of the DNA double helix. Upon binding, the PBD dimer forms covalent bonds with the N2 positions of guanine bases on opposite DNA strands, creating an interstrand cross-link (ICL). Unlike traditional alkylating agents, PBD dimers cause minimal distortion to the DNA helix, which allows the adducts to remain hidden from certain DNA repair mechanisms, leading to persistent DNA damage. This stalling of replication forks and inhibition of transcription eventually triggers the DNA damage response and leads to cell cycle arrest and apoptosis. Consequently, this target is highly relevant in oncology, particularly as the cytotoxic payload for antibody-drug conjugates (ADCs) like loncastuximab tesirine, which are used to treat various lymphomas and leukemias.

Other names

5′-PuGATCPy-3′ DNA sequencePBD dimer binding siteDNA minor groove interstrand cross-link sitePyrrolobenzodiazepine dimer recognition sequence

Covalent binding to the N2 position of guanines on opposite DNA strands within the minor groove to form interstrand cross-links, thereby inhibiting DNA replication and transcription.