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PDBsum entry 1osf
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystal structure and molecular modeling of 17-Dmag in complex with human hsp90.
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Authors
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J.M.Jez,
J.C.Chen,
G.Rastelli,
R.M.Stroud,
D.V.Santi.
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Ref.
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Chem Biol, 2003,
10,
361-368.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 4.
Figure 4. Interactions between 17-DMAG and Hsp90Schematic
drawing of interactions between 17-DMAG and the ATP binding site
of human Hsp90α. Hydrogen bonds are shown as dotted lines with
distances given in angstroms.
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Figure 5.
Figure 5. Molecular Dynamics of the Conformational Change
of GeldanamycinSuperimposition of averaged structures collected
during the 800 ps TMD simulation that converts the free into the
bound form of geldanamycin. In the superimpositions, the initial
structures are colored in yellow, and the final structures are
colored in cyan. The intermediate conformations are explicitly
shown. For clarity, only the polar hydrogens are shown.
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The above figures are
reprinted
by permission from Cell Press:
Chem Biol
(2003,
10,
361-368)
copyright 2003.
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