8F2K

Structure of yeast F1-ATPase determined with 100 micromolar cruentaren A

Summary for 8F2K

• Entry DOI: 10.2210/pdb8f2k/pdb
• EMDB information: 28818
• Descriptor: ATP synthase subunit alpha, ATP synthase subunit beta, ATP synthase subunit gamma, ... (6 entities in total)
• Functional Keywords: f1-atpase, atp synthase, cruentaren a, drug development, hydrolase
• Biological source: Saccharomyces cerevisiae (baker's yeast); More
• Total number of polymer chains: 7
• Total formula weight: 342504.27

Authors

Guo, H.,Rubinstein, J.L. (deposition date: 2022-11-08, release date: 2023-04-05, Last modification date: 2024-04-24)

Primary citation

Dou, X.,Guo, H.,D'Amico, T.,Abdallah, L.,Subramanian, C.,Patel, B.A.,Cohen, M.,Rubinstein, J.L.,Blagg, B.S.J.
CryoEM Structure with ATP Synthase Enables Late-Stage Diversification of Cruentaren A.
Chemistry, 29:e202300262-e202300262, 2023

PubMed Abstract: Cruentaren A is a natural product that exhibits potent antiproliferative activity against various cancer cell lines, yet its binding site within ATP synthase remained unknown, thus limiting the development of improved analogues as anticancer agents. Herein, we report the cryogenic electron microscopy (cryoEM) structure of cruentaren A bound to ATP synthase, which allowed the design of new inhibitors through semisynthetic modification. Examples of cruentaren A derivatives include a trans-alkene isomer, which was found to exhibit similar activity to cruentaren A against three cancer cell lines as well as several other analogues that retained potent inhibitory activity. Together, these studies provide a foundation for the generation of cruentaren A derivatives as potential therapeutics for the treatment of cancer.

PubMed: 36867738
DOI: 10.1002/chem.202300262

Experimental method

ELECTRON MICROSCOPY (2.9 Å)