title: Identification of a polyoxometalate inhibitor of the DNA binding activity of Sox2.
abstract: Aberrant expression of transcription factors is a frequent cause of disease, yet drugs that modulate transcription factor protein-DNA interactions are presently unavailable. To this end, the chemical tractability of the DNA binding domain of the stem cell inducer and oncogene Sox2 was explored in a high-throughput fluorescence anisotropy screen. The screening revealed a Dawson polyoxometalate (K(6)[P(2)Mo(18)O(62)]) as a direct and nanomolar inhibitor of the DNA binding activity of Sox2. The Dawson polyoxometalate (Dawson-POM) was found to be selective for Sox2 and related Sox-HMG family members when compared to unrelated paired and zinc finger DNA binding domains. [(15)N,(1)H]-Transverse relaxation optimized spectroscopy (TROSY) experiments coupled with docking studies suggest an interaction site of the POM on the Sox2 surface that enabled the rationalization of its inhibitory activity. The unconventional molecular scaffold of the Dawson-POM and its inhibitory mode provides strategies for the development of drugs that modulate transcription factors.
authors.affiliation: Laboratory for Structural Biochemistry, Genome Institute of Singapore, Singapore 138672.
authors.forename: Kamesh
authors.initials: K
authors.lastname: Narasimhan
authors.forename: Shubhadra
authors.initials: S
authors.lastname: Pillay
authors.forename: Nor Rizal
authors.initials: NR
authors.lastname: Bin Ahmad
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bikadi
authors.forename: Eszter
authors.initials: E
authors.lastname: Hazai
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.forename: Prasanna R
authors.initials: PR
authors.lastname: Kolatkar
authors.forename: Konstantin
authors.initials: K
authors.lastname: Pervushin
authors.forename: Ralf
authors.initials: R
authors.lastname: Jauch
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D005454:Fluorescence Polarization; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D055748:SOXB1 Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013499:Surface Properties; D017973:Tungsten Compounds / Q000737:chemistry / Q000494:pharmacology*; D000099294:Polyoxometalates
chemical_list: D004247:DNA; D055748:SOXB1 Transcription Factors; D017973:Tungsten Compounds; C527782:SOX2 protein, human; C102296:polyoxometalate I; D000099294:Polyoxometalates