5NXQ

Crystal structure of the carboxy-terminal domain of yeast Ctf4 bound to a stapled Sld5 CIP

Summary for 5NXQ

• Entry DOI: 10.2210/pdb5nxq/pdb
• Related: 4C8S 4C95
• Descriptor: DNA polymerase alpha-binding protein, MET-ASP-ILE-UA1-ILE-ASP-ASP-ILE-LEU-UA2-GLU-LEU-ASP-LYS-GLU, GLYCEROL, ... (4 entities in total)
• Functional Keywords: dna replication, adaptor protein, beta-propeller domain, replication
• Biological source: Saccharomyces cerevisiae (Baker's yeast); More
• Cellular location: Nucleus: Q01454
• Total number of polymer chains: 5
• Total formula weight: 168315.01

Authors

Wu, Y.,Pellegrini, L. (deposition date: 2017-05-10, release date: 2017-08-30, Last modification date: 2024-10-23)

Primary citation

Wu, Y.,Villa, F.,Maman, J.,Lau, Y.H.,Dobnikar, L.,Simon, A.C.,Labib, K.,Spring, D.R.,Pellegrini, L.
Targeting the Genome-Stability Hub Ctf4 by Stapled-Peptide Design.
Angew. Chem. Int. Ed. Engl., 56:12866-12872, 2017

PubMed Abstract: The 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, which links DNA replication, repair, and chromosome segregation, represents a novel target for the synthetic lethality approach. Herein, we report the design, optimization, and validation of double-click stapled peptides encoding the Ctf4-interacting peptide (CIP) of the replicative helicase subunit Sld5. By screening stapling positions in the Sld5 CIP, we identified an unorthodox i,i+6 stapled peptide with improved, submicromolar 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 α 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.

PubMed: 28815832
DOI: 10.1002/anie.201705611

Experimental method

X-RAY DIFFRACTION (2.413 Å)