Cryogenic Human Hsp90a-NTD bound to EC144

Experimental Data Snapshot

  • Resolution: 1.45 Å
  • R-Value Free: 0.184 
  • R-Value Work: 0.157 
  • R-Value Observed: 0.158 

Starting Model: experimental
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Ligand Structure Quality Assessment 

This is version 1.1 of the entry. See complete history


Water Networks Repopulate Protein-Ligand Interfaces with Temperature.

Stachowski, T.R.Vanarotti, M.Seetharaman, J.Lopez, K.Fischer, M.

(2022) Angew Chem Int Ed Engl 61: e202112919-e202112919

  • DOI: https://doi.org/10.1002/anie.202112919
  • Primary Citation of Related Structures:  
    7S8Y, 7S8Z, 7S90, 7S95, 7S98, 7S99, 7S9F, 7S9G, 7S9H, 7S9I

  • PubMed Abstract: 

    High-resolution crystal structures highlight the importance of water networks in protein-ligand interactions. However, as these are typically determined at cryogenic temperature, resulting insights may be structurally precise but not biologically accurate. By collecting 10 matched room-temperature and cryogenic datasets of the biomedical target Hsp90α, we identified changes in water networks that impact protein conformations at the ligand binding interface. Water repositioning with temperature repopulates protein ensembles and ligand interactions. We introduce Flipper conformational barcodes to identify temperature-sensitive regions in electron density maps. This revealed that temperature-responsive states coincide with ligand-responsive regions and capture unique binding signatures that disappear upon cryo-cooling. Our results have implications for discovering Hsp90 selective ligands, and, more generally, for the utility of hidden protein and water conformations in drug discovery.

  • Organizational Affiliation

    Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Heat shock protein HSP 90-alpha237Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P07900 (Homo sapiens)
Explore P07900 
Go to UniProtKB:  P07900
GTEx:  ENSG00000080824 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP07900
Sequence Annotations
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7PP (Subject of Investigation/LOI)
Query on 7PP

Download Ideal Coordinates CCD File 
B [auth A]5-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methylpent-4-yn-2 -ol
C21 H24 Cl N5 O2
Query on MG

Download Ideal Coordinates CCD File 
Experimental Data & Validation

Experimental Data

  • Resolution: 1.45 Å
  • R-Value Free: 0.184 
  • R-Value Work: 0.157 
  • R-Value Observed: 0.158 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.381α = 90
b = 90.196β = 90
c = 97.719γ = 90
Software Package:
Software NamePurpose
Cootmodel building
xia2data reduction
Aimlessdata scaling

Structure Validation

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Ligand Structure Quality Assessment 

Entry History & Funding Information

Deposition Data

Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United States1R35GM142772-01

Revision History  (Full details and data files)

  • Version 1.0: 2022-08-03
    Type: Initial release
  • Version 1.1: 2023-10-18
    Changes: Data collection, Refinement description