4AWP

Complex of HSP90 ATPase domain with tropane derived inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.82 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.207 

wwPDB Validation   3D Report Full Report


This is version 1.0 of the entry. See complete history


Literature

Discovery of Xl888: A Novel Tropane-Derived Small Molecule Inhibitor of Hsp90.

Bussenius, J.Blazey, C.M.Aay, N.Anand, N.K.Arcalas, A.Baik, T.Bowles, O.J.Buhr, C.A.Costanzo, S.Curtis, J.K.Defina, S.C.Dubenko, L.Heuer, T.S.Huang, P.Jaeger, C.Joshi, A.Kennedy, A.R.Kim, A.I.Lara, K.Lee, J.Li, J.Lougheed, J.C.Ma, S.Malek, S.Manalo, J.C.Martini, J.F.Mcgrath, G.Nicoll, M.Nuss, J.M.Pack, M.Peto, C.J.Tsang, T.H.Wang, L.Womble, S.W.Yakes, M.Zhang, W.Rice, K.D.

(2012) Bioorg Med Chem Lett 22: 5396

  • DOI: https://doi.org/10.1016/j.bmcl.2012.07.052
  • Primary Citation of Related Structures:  
    4AWO, 4AWP, 4AWQ

  • PubMed Abstract: 

    With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens.


  • Organizational Affiliation

    Exelixis, Inc., 220 East Grand Ave., South San Francisco, CA 94080, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HEAT SHOCK PROTEIN HSP 90-ALPHA
A, B
230Homo sapiensMutation(s): 0 
EC: 3.6.4.10
UniProt & NIH Common Fund Data Resources
Find proteins for P07900 (Homo sapiens)
Explore P07900 
Go to UniProtKB:  P07900
PHAROS:  P07900
GTEx:  ENSG00000080824 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP07900
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
99A
Query on 99A

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
N-{(3-endo)-8-[5-(benzylcarbamoyl)pyridin-2-yl]-8-azabicyclo[3.2.1]oct-3-yl}-2,5-dimethylbenzene-1,4-dicarboxamide
C30 H33 N5 O3
CHQGBLRVADDSPY-BKFWDETESA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
99A BindingDB:  4AWP IC50: min: 81, max: 1.00e+4 (nM) from 2 assay(s)
PDBBind:  4AWP IC50: 81 (nM) from 1 assay(s)
Binding MOAD:  4AWP IC50: 81 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.82 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.207 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 44.307α = 70.48
b = 56.904β = 87.2
c = 57.457γ = 69.02
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-08-29
    Type: Initial release