5J8M

Crystal Structure of Hsp90-alpha N-domain L107A mutant in complex with 5-(5-Bromo-2,4-dihydroxy-phenyl)-4-(2-fluoro-phenyl)-2,4-dihydro-[1,2,4]triazol-3-one


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.189 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Protein conformational flexibility modulates kinetics and thermodynamics of drug binding.

Amaral, M.Kokh, D.B.Bomke, J.Wegener, A.Buchstaller, H.P.Eggenweiler, H.M.Matias, P.Sirrenberg, C.Wade, R.C.Frech, M.

(2017) Nat Commun 8: 2276-2276

  • DOI: https://doi.org/10.1038/s41467-017-02258-w
  • Primary Citation of Related Structures:  
    5J20, 5J27, 5J2V, 5J2X, 5J64, 5J6L, 5J6M, 5J6N, 5J80, 5J82, 5J86, 5J8M, 5J8U, 5J9X

  • PubMed Abstract: 

    Structure-based drug design has often been restricted by the rather static picture of protein-ligand complexes presented by crystal structures, despite the widely accepted importance of protein flexibility in biomolecular recognition. Here we report a detailed experimental and computational study of the drug target, human heat shock protein 90, to explore the contribution of protein dynamics to the binding thermodynamics and kinetics of drug-like compounds. We observe that their binding properties depend on whether the protein has a loop or a helical conformation in the binding site of the ligand-bound state. Compounds bound to the helical conformation display slow association and dissociation rates, high-affinity and high cellular efficacy, and predominantly entropically driven binding. An important entropic contribution comes from the greater flexibility of the helical relative to the loop conformation in the ligand-bound state. This unusual mechanism suggests increasing target flexibility in the bound state by ligand design as a new strategy for drug discovery.


  • Organizational Affiliation

    iBET - Instituto de Biologia Experimental e Tecnológica, Oeiras, 2780-157, Portugal. marta.amaral@sanofi.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Heat shock protein HSP 90-alpha
A, B
225Homo sapiensMutation(s): 0 
Gene Names: HSP90AA1HSP90AHSPC1HSPCA
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
6DL
Query on 6DL

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
5-(5-Bromo-2,4-dihydroxy-phenyl)-4-(2-fluoro-phenyl)-2,4-dihydro-[1,2,4]triazol-3-one
C14 H9 Br F N3 O3
WTHWBOWCSOCLLT-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6DL Binding MOAD:  5J8M Kd: 64 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.189 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 129.79α = 90
b = 65.19β = 130.11
c = 88.01γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
IMI-K4DD155366

Revision History  (Full details and data files)

  • Version 1.0: 2017-12-06
    Type: Initial release
  • Version 1.1: 2018-01-24
    Changes: Database references
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Refinement description