A small molecule inhibitor selective for a variant ATP-binding site of the chaperonin GroEL

Eli Chapman, George W. Farr, Krystyna Furtak, Arthur L. Horwich

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


The chaperonin GroEL is a megadalton-sized molecular machine that plays an essential role in the bacterial cell assisting protein folding to the native state through actions requiring ATP binding and hydrolysis. A combination of medicinal chemistry and genetics has been employed to generate an orthogonal pair, a small molecule that selectively inhibits ATPase activity of a GroEL ATP-binding pocket variant. An initial screen of kinase-directed inhibitors identified an active pyrazolo-pyrimidine scaffold that was iteratively modified and screened against a collective of GroEL nucleotide pocket variants to identify a cyclopentyl carboxamide derivative, EC3016, that specifically inhibits ATPase activity and protein folding by the GroEL mutant, I493C, involving a side chain positioned near the base of ATP. This orthogonal pair will enable in vitro studies of the action of ATP in triggering activation of GroEL-mediated protein folding and might enable further studies of GroEL action in vivo. The approach originated for studying kinases by Shokat and his colleagues may thus also be used to study large macromolecular machines.

Original languageEnglish (US)
Pages (from-to)811-813
Number of pages3
JournalBioorganic and Medicinal Chemistry Letters
Issue number3
StatePublished - Feb 1 2009


  • ATPase inhibitor
  • Chaperone
  • Chaperonin
  • Chemical genetics
  • GroEL

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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