2YGA

E88G-N92L Mutant of N-Term HSP90 complexed with Geldanamycin

Summary for 2YGA

• Entry DOI: 10.2210/pdb2yga/pdb
• Related: 1A4H 1AH6 1AH8 1AM1 1AMW 1BGQ 1HK7 1US7 1USU 1USV 1ZW9 1ZWH 2AKP 2BRC 2BRE 2CG9 2CGE 2CGF 2IWS 2IWU 2IWX 2VW5 2VWC 2WEP 2WEQ 2WER 2XD6 2XX2 2XX4 2XX5
• Descriptor: ATP-DEPENDENT MOLECULAR CHAPERONE HSP82, GELDANAMYCIN (3 entities in total)
• Functional Keywords: chaperone
• Biological source: SACCHAROMYCES CEREVISIAE (BAKER'S YEAST)
• Cellular location: Cytoplasm: P02829
• Total number of polymer chains: 1
• Total formula weight: 25361.03

Authors

Roe, S.M.,Prodromou, C.,Pearl, L.H. (deposition date: 2011-04-12, release date: 2011-11-16, Last modification date: 2024-05-01)

Primary citation

Millson, S.H.,Chua, C.,Roe, S.M.,Polier, S.,Solovieva, S.,Pearl, L.H.,Sim, T.,Prodromou, C.,Piper, P.W.
Features of the Streptomyces Hygroscopicus Htpg Reveal How Partial Geldanamycin Resistance Can Arise with Mutation to the ATP Binding Pocket of a Eukaryotic Hsp90.
Faseb J., 25:3828-, 2011

PubMed Abstract: Much attention is focused on the benzoquinone ansamycins as anticancer agents, with several derivatives of the natural product geldanamycin (GdA) now in clinical trials. These drugs are selective inhibitors of Hsp90, a molecular chaperone vital for many of the activities that drive cancer progression. Mutational changes to their interaction site, the extremely conserved ATP binding site of Hsp90, would mostly be predicted to inactivate the chaperone. As a result, drug resistance should not arise readily this way. Nevertheless, Streptomyces hygroscopicus, the actinomycete that produces GdA, has evolved an Hsp90 family protein (HtpG) that lacks GdA binding. It is altered in certain of the highly conserved amino acids making contacts to this antibiotic in crystal structures of GdA bound to eukaryotic forms of Hsp90. Two of these amino acid changes, located on one side of the nucleotide-binding cleft, weakened GdA/Hsp90 binding and conferred partial GdA resistance when inserted into the endogenous Hsp90 of yeast cells. Crystal structures revealed their main effect to be a weakening of interactions with the C-12 methoxy group of the GdA ansamycin ring. This is the first study to demonstrate that partial GdA resistance is possible by mutation within the ATP binding pocket of Hsp90.

PubMed: 21778327
DOI: 10.1096/FJ.11-188821

Experimental method

X-RAY DIFFRACTION (2.37 Å)