1osf

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Revision as of 16:29, 12 November 2007

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spinqualitylabelsall models 1osf, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Human Hsp90 in complex with 17-desmethoxy-17-N,N-Dimethylaminoethylamino-Geldanamycin

Overview

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.

About this Structure

1OSF is a Single protein structure of sequence from Homo sapiens with KOS, MPD and ACY as ligands. Full crystallographic information is available from OCA.

Reference

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

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