Posttranslational modification and conformational state of heat shock protein 90 differentially affect binding of chemically diverse small molecule inhibitors.

摘要: // Kristin Beebe 1 , Mehdi Mollapour 1,7,8 Bradley Scroggins Chrisostomos Prodromou 2 Wanping Xu Mari Tokita Tony Taldone 3 Lester Pullen 4 Bettina K. Zierer 5 Min-Jung Lee 6 Jane Trepel Johannes Buchner Daniel Bolon Gabriela Chiosis Leonard Neckers Urologic Oncology Branch, Center for Cancer Research, National Institute, Bethesda, MD, USA University of Sussex, John Maynard Smith Building, Falmer, Brighton, UK Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Center, New York, NY, Massachusetts Medical School, Department Biochemistry Pharmacology, Worcester, MA, Technische Universitat Munchen, Chemistry, Garching, Munich, Germany 7 Biology, SUNY Upstate University, Syracuse, 8 Urology, Correspondence: Len Neckers, email: Keywords : Hsp90, posttranslational modification, phosphorylation, drug binding, Hsp90 inhibitor Received June 14, 2013 Accepted July 5, Published 7, Abstract Heat shock protein 90 (Hsp90) is an essential molecular chaperone in eukaryotes that facilitates the conformational maturation function a diverse clientele, including aberrant and/or over-expressed proteins are involved cancer growth survival. A role supporting homeostasis cells has buoyed interest utility inhibitors as anti-cancer drugs. Despite fact all clinically evaluated target identical nucleotide-binding pocket N domain chaperone, precise determinants affect binding cellular environment remain unclear, it possible chemically distinct may not share similar preferences. Here we demonstrate two unrelated inhibitors, benzoquinone ansamycin geldanamycin purine analog PU-H71, select overlapping but subpopulations total even though both bind to amino terminal nucleotide prevent dimerization. Our data also suggest PU-H71 able access broader range undimerized conformations than less affected by consistent with its more potent anti-tumor activity. complete understanding impact milieu on small molecule should facilitate their effective use clinic.