3B24

Hsp90 alpha N-terminal domain in complex with an aminotriazine fragment molecule


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.188 
  • R-Value Work: 0.161 
  • R-Value Observed: 0.163 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Lead generation of heat shock protein 90 inhibitors by a combination of fragment-based approach, virtual screening, and structure-based drug design

Miura, T.Fukami, T.A.Hasegawa, K.Ono, N.Suda, A.Shindo, H.Yoon, D.O.Kim, S.J.Na, Y.J.Aoki, Y.Shimma, N.Tsukuda, T.Shiratori, Y.

(2011) Bioorg Med Chem Lett 21: 5778-5783

  • DOI: https://doi.org/10.1016/j.bmcl.2011.08.001
  • Primary Citation of Related Structures:  
    3B24, 3B25, 3B26, 3B27, 3B28

  • PubMed Abstract: 

    Heat shock protein 90 (Hsp90) is a molecular chaperone which regulates maturation and stabilization of its substrate proteins, known as client proteins. Many client proteins of Hsp90 are involved in tumor progression and survival and therefore Hsp90 can be a good target for developing anticancer drugs. With the aim of efficiently identifying a new class of orally available inhibitors of the ATP binding site of this protein, we conducted fragment screening and virtual screening in parallel against Hsp90. This approach quickly identified 2-aminotriazine and 2-aminopyrimidine derivatives as specific ligands to Hsp90 with high ligand efficiency. In silico evaluation of the 3D X-ray Hsp90 complex structures of the identified hits allowed us to promptly design CH5015765, which showed high affinity for Hsp90 and antitumor activity in human cancer xenograft mouse models.


  • Organizational Affiliation

    Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. miuratka@chugai-pharm.co.jp


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Heat shock protein HSP 90-alpha
A, B
229Homo sapiensMutation(s): 0 
Gene Names: HSP90AA1
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
Binding Affinity Annotations 
IDSourceBinding Affinity
B2J BindingDB:  3B24 Kd: 4.20e+4 (nM) from 1 assay(s)
PDBBind:  3B24 Kd: 4.20e+4 (nM) from 1 assay(s)
Binding MOAD:  3B24 Kd: 4.20e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.188 
  • R-Value Work: 0.161 
  • R-Value Observed: 0.163 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 64.193α = 90
b = 88.51β = 90
c = 98.523γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
TNTrefinement
PDB_EXTRACTdata extraction
ADSCdata collection
HKL-2000data reduction
HKL-2000data scaling
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-09-14
    Type: Initial release
  • Version 1.1: 2013-06-19
    Changes: Database references
  • Version 1.2: 2017-10-11
    Changes: Refinement description
  • Version 1.3: 2024-03-13
    Changes: Data collection, Database references, Derived calculations