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|1osf, resolution 1.75Å ()|
Human Hsp90 in complex with 17-desmethoxy-17-N,N-Dimethylaminoethylamino-Geldanamycin
Hsp90 is an attractive chemotherapeutic target because it chaperones the folding of proteins found in multiple signal transduction pathways. We describe the 1.75 A resolution crystal structure of human Hsp90 alpha (residues 9-236) complexed with 17-desmethoxy-17-N,N-dimethylaminoethylamino-geldanamycin (17-DMAG). The structure revealed an altered set of interactions between the 17-substituent and the protein compared to geldanamycin and the 17-dimethylaminoethyl moiety pointing into solvent, but otherwise was similar to that reported for the complex with geldanamycin. Targeted molecular dynamics simulations and energetic analysis indicate that geldanamycin undergoes two major conformational changes when it binds Hsp90, with the key step of the conversion being the trans to cis conformational change of the macrocycle amide bond. We speculate that 17-DMAG analogs constrained to a cis-amide in the ground state could provide a significant increase in affinity for Hsp90.
Crystal structure and molecular modeling of 17-DMAG in complex with human Hsp90., Jez JM, Chen JC, Rastelli G, Stroud RM, Santi DV, Chem Biol. 2003 Apr;10(4):361-8. PMID:12725864
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
- Jez JM, Chen JC, Rastelli G, Stroud RM, Santi DV. Crystal structure and molecular modeling of 17-DMAG in complex with human Hsp90. Chem Biol. 2003 Apr;10(4):361-8. PMID:12725864