Structural highlights
Function
[CTF4_YEAST] Accessory factor for DNA replication. It plays a role in accurately duplicating the genome in vivo.
Publication Abstract from PubMed
Exploitation of synthetic lethality by small-molecule targeting of pathways that maintain genomic stability is an attractive chemotherapeutic approach. The Ctf4/AND-1 protein hub that links DNA replication, repair and chromosome segregation, represents a novel target for the synthetic lethality approach. Here we report the design, optimization, and validation of double-click stapled peptides encoding the Ctf4-interacting peptide (CIP) of the replicative helicase subunit Sld5. Screening stapling positions in the Sld5 CIP, we identified an unorthodox i,i+6 stapled peptide with improved, sub-micromolar binding to Ctf4. The mode of interaction with Ctf4 was confirmed by a crystal structure of the stapled Sld5 peptide bound to Ctf4. The stapled Sld5 peptide was able to displace the Ctf4-partner DNA polymerase alpha from the replisome in yeast extracts. Our study provides proof-of-principle evidence for the development of small-molecule inhibitors of the human-CTF4 orthologue AND-1.
Targeting the genome stability hub Ctf4 by stapled-peptide design.,Wu Y, Villa F, Maman J, Dobnikar L, Lau YH, Simon AC, Labib K, Spring DR, Pellegrini L Angew Chem Int Ed Engl. 2017 Aug 17. doi: 10.1002/anie.201705611. PMID:28815832[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wu Y, Villa F, Maman J, Dobnikar L, Lau YH, Simon AC, Labib K, Spring DR, Pellegrini L. Targeting the genome stability hub Ctf4 by stapled-peptide design. Angew Chem Int Ed Engl. 2017 Aug 17. doi: 10.1002/anie.201705611. PMID:28815832 doi:http://dx.doi.org/10.1002/anie.201705611
