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Towards a minimal motif for artificial transcriptional activators

Ansari, Aseem Z. and Mapp, Anna K. and Nguyen, Doan H. and Dervan, Peter B. and Ptashne, Mark (2001) Towards a minimal motif for artificial transcriptional activators. Chemistry and Biology, 8 (6). pp. 583-92. ISSN 1074-5521.

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Background: Most transcriptional activators minimally comprise two functional modules, one for DNA binding and the other for activation. Several activators also bear an oligomerization region and bind DNA as dimers or higher order oligomers. In a previous study we substituted these domains of a protein activator with synthetic counterparts [Mapp et al., Proc. Natl. Acad. Sci. USA 97 (2000) 3930–3935]. An artificial transcriptional activator, 4.2 kDa in size, comprised of a DNA binding hairpin polyamide tethered to a 20 residue activating peptide (AH) was shown to stimulate promoter specific transcription [Mapp et al., Proc. Natl. Acad. Sci. USA 97 (2000) 3930–3935]. The question arises as to the general nature and the versatility of this minimal activator motif and whether smaller ligands can be designed which maintain potent activation function. Results: Here we have replaced the 20 amino acid AH peptide with eight or 16 residues derived from the activation domain of the potent viral activator VP16. The 16 residue activation module coupled to the polyamide activated transcription over two-fold better than the analogous AH conjugate. Altering the site of attachment of the activation module on the polyamide allowed reduction of the intervening linker from 36 atoms to eight without significant diminution of the activation potential. In this study we also exchanged the polyamide to target a different sequence without compromising the activation function further demonstrating the generality of this design. Conclusions: The polyamide activator conjugates described here represent a class of DNA binding ligands which are tethered to a second functional moiety, viz. an activation domain, that recruits elements of the endogenous transcriptional machinery. Our results define the minimal structural elements required to construct artificial, small molecule activators. If such activators are cell-permeable and can be targeted to designated sites in the genome, this series of conjugates may then serve as a tool to study mechanistic aspects of transcriptional regulation and eventually to modulate gene expression relevant to human diseases.

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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2001 Elsevier Science Ltd. Received 24 January 2001; revisions requested 9 March 2001; revisions received 30 March 2001; accepted 20 April 2001. First published online 8 May 2001. We are grateful to the National Institutes of Health for research support.
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Subject Keywords:Small molecule activator; Hairpin polyamide; Chemical regulator; Targeted gene control
Issue or Number:6
Record Number:CaltechAUTHORS:20160510-082726586
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Official Citation:Aseem Z Ansari, Anna K Mapp, Doan H Nguyen, Peter B Dervan, Mark Ptashne, Towards a minimal motif for artificial transcriptional activators, Chemistry & Biology, Volume 8, Issue 6, June 2001, Pages 583-592, ISSN 1074-5521, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66823
Deposited By: Victoria Brennan
Deposited On:18 May 2016 19:11
Last Modified:26 Nov 2019 11:15

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