6RLZ

Crystal Structure of 14-3-3zeta in complex with a macrocyclic 8-mer peptide derived from ExoS


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.70 Å
  • R-Value Free: 0.292 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.223 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history

Re-refinement Note

This entry reflects an alternative modeling of the original data in: 5j31 4n7y 4n84 4n7g


Literature

Adapting free energy perturbation simulations for large macrocyclic ligands: how to dissect contributions from direct binding and free ligand flexibility.

Wallraven, K.Holmelin, F.L.Glas, A.Hennig, S.Frolov, A.I.Grossmann, T.N.

(2020) Chem Sci 11: 2269-2276

  • DOI: https://doi.org/10.1039/c9sc04705k
  • Primary Citation of Related Structures:  
    6RLZ

  • PubMed Abstract: 

    Large and flexible ligands gain increasing interest in the development of bioactive agents. They challenge the applicability of computational ligand optimization strategies originally developed for small molecules. Free energy perturbation (FEP) is often used for predicting binding affinities of small molecule ligands, however, its use for more complex ligands remains limited. Herein, we report the structure-based design of peptide macrocycles targeting the protein binding site of human adaptor protein 14-3-3. We observe a surprisingly strong dependency of binding affinities on relatively small variations in substituent size. FEP was performed to rationalize observed trends. To account for insufficient convergence of FEP, restrained calculations were performed and complemented with extensive REST MD simulations of the free ligands. These calculations revealed that changes in affinity originate both from altered direct interactions and conformational changes of the free ligand. In addition, MD simulations provided the basis to rationalize unexpected trends in ligand lipophilicity. We also verified the anticipated interaction site and binding mode for one of the high affinity ligands by X-ray crystallography. The introduced fully-atomistic simulation protocol can be used to rationalize the development of structurally complex ligands which will support future ligand maturation efforts.


  • Organizational Affiliation

    Department of Chemistry & Pharmaceutical Sciences , VU University Amsterdam , De Boelelaan 1083 , 1081 HV Amsterdam , The Netherlands . Email: t.n.grossmann@vu.nl.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
14-3-3 protein zeta/delta
A, B
230Homo sapiensMutation(s): 0 
Gene Names: YWHAZ
UniProt & NIH Common Fund Data Resources
Find proteins for P63104 (Homo sapiens)
Explore P63104 
Go to UniProtKB:  P63104
PHAROS:  P63104
GTEx:  ENSG00000164924 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP63104
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
EtMe
C, D
8Pseudomonas aeruginosaMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.70 Å
  • R-Value Free: 0.292 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.223 
  • Space Group: P 64
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 98.8α = 90
b = 98.8β = 90
c = 94.8γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
European Research Council--

Revision History  (Full details and data files)

  • Version 1.0: 2020-03-18
    Type: Initial release
  • Version 1.1: 2020-03-25
    Changes: Database references