2XX2

Macrolactone Inhibitor bound to HSP90 N-term


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.207 

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This is version 2.0 of the entry. See complete history


Literature

Targeting the Hsp90 Molecular Chaperone with Novel Macrolactams. Synthesis, Structural, Binding, and Cellular Studies.

Day, J.E.Sharp, S.Y.Rowlands, M.G.Aherne, W.Hayes, A.Raynaud, F.I.Lewis, W.Roe, S.M.Prodromou, C.Pearl, L.H.Workman, P.Moody, C.J.

(2011) ACS Chem Biol 6: 1339

  • DOI: https://doi.org/10.1021/cb200196e
  • Primary Citation of Related Structures:  
    2XX2, 2XX4, 2XX5

  • PubMed Abstract: 

    A series of resorcylic acid macrolactams, nitrogen analogues of the naturally occurring macrolactone radicicol, have been prepared by chemical synthesis and evaluated as inhibitors of heat shock protein 90 (Hsp90), an emerging attractive target for novel cancer therapeutic agents. The synthesis involves, as key steps, ring opening of an isocoumarin intermediate, followed by a ring-closing metathesis reaction to form the macrocycle. Subsequent manipulation of the ester group into a range of amides allows access to a range of new macrolactams following deprotection of the two phenolic groups. These new resorcylic acid lactams exhibit metabolic stability greater than that of related lactone counterparts, while co-crystallization of three macrolactams with the N-terminal domain ATP site of Hsp90 confirms that they bind in a similar way to the natural product radicicol and to our previous synthetic lactone analogues. Interestingly, however, in the case of the N-benzylamide, additional binding to a hydrophobic pocket of the protein was observed. In biological assays, the new macrocyclic lactams exhibit a biological profile equivalent or superior to that of the related lactones and show the established molecular signature of Hsp90 inhibitors in human colon cancer cells.


  • Organizational Affiliation

    School of Chemistry, University of Nottingham, University Park, U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ATP-DEPENDENT MOLECULAR CHAPERONE HSP82
A, B, C, D
214Saccharomyces cerevisiaeMutation(s): 0 
UniProt
Find proteins for P02829 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P02829 
Go to UniProtKB:  P02829
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP02829
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
13C PDBBind:  2XX2 IC50: 50 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.207 
  • Space Group: P 43
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 104.5α = 90
b = 104.5β = 90
c = 109.57γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-11-16
    Type: Initial release
  • Version 1.1: 2011-12-28
    Changes: Other
  • Version 2.0: 2023-12-20
    Changes: Atomic model, Data collection, Database references, Derived calculations, Other, Refinement description