6AX4

Plk-1 polo-box domain in complex with histidine N(tau)-cyclized Macrocycle 5b.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.166 
  • R-Value Work: 0.132 
  • R-Value Observed: 0.134 

wwPDB Validation   3D Report Full Report


This is version 2.0 of the entry. See complete history


Literature

Histidine N( tau )-cyclized macrocycles as a new genre of polo-like kinase 1 polo-box domain-binding inhibitors.

Hymel, D.Grant, R.A.Tsuji, K.Yaffe, M.B.Burke Jr., T.R.

(2018) Bioorg Med Chem Lett 28: 3202-3205

  • DOI: https://doi.org/10.1016/j.bmcl.2018.08.018
  • Primary Citation of Related Structures:  
    6AX4

  • PubMed Abstract: 

    Transition toward peptide mimetics of reduced size is an important objective of peptide macrocyclization. We have previously shown that PLH SpT (2a) (where H indicates the presence of a -(CH 2 ) 8 Ph group at the N(π) position and pT indicates phosphothreonine) is an extremely high affinity ligand of the polo-like kinase 1 (Plk1) polo-box domain (PBD). Herein we report that C-terminal macrocyclization of 2a employing N(π),N(τ)-bis-alkylated His residues as ring junctions can be achieved in a very direct fashion. The resulting macrocycles are highly potent in biochemical assays and maintain good target selectivity for the Plk1 PBD versus the PBDs of Plk2 and Plk3. Importantly, as exemplified by 5d, our current approach permits deletion of the N-terminal "Pro-Leu" motif to yield tripeptide ligands with decreased molecular weight, which retain high affinity and show improved target selectivity. These findings could fundamentally impact the future development of peptide macrocycles in general and Plk1 PBD-binding peptide mimetics in particular.


  • Organizational Affiliation

    Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase PLK1237Homo sapiensMutation(s): 0 
Gene Names: PLK1PLK
EC: 2.7.11.21
UniProt & NIH Common Fund Data Resources
Find proteins for P53350 (Homo sapiens)
Explore P53350 
Go to UniProtKB:  P53350
PHAROS:  P53350
GTEx:  ENSG00000166851 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP53350
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
histidine N(tau)-cyclized Macrocycle 5bB [auth C]5synthetic constructMutation(s): 0 
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
AML
Query on AML

Download Ideal Coordinates CCD File 
C
AMYLAMINE
C5 H13 N
DPBLXKKOBLCELK-UHFFFAOYSA-N
Modified Residues  3 Unique
IDChains TypeFormula2D DiagramParent
56A
Query on 56A
B [auth C]L-PEPTIDE LINKINGC20 H29 N3 O2HIS
N7P
Query on N7P
B [auth C]L-PEPTIDE LINKINGC7 H11 N O3PRO
TPO
Query on TPO
B [auth C]L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.166 
  • R-Value Work: 0.132 
  • R-Value Observed: 0.134 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 35.449α = 90
b = 51.294β = 100.84
c = 58.034γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
HKL-2000data scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)United StatesR01-ES015339-06
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesZIA BC 006198

Revision History  (Full details and data files)

  • Version 1.0: 2018-09-12
    Type: Initial release
  • Version 1.1: 2018-09-19
    Changes: Data collection, Database references
  • Version 1.2: 2018-10-17
    Changes: Data collection, Database references
  • Version 1.3: 2019-02-20
    Changes: Author supporting evidence, Data collection
  • Version 1.4: 2019-12-18
    Changes: Author supporting evidence
  • Version 1.5: 2022-03-23
    Changes: Author supporting evidence, Database references
  • Version 1.6: 2023-10-04
    Changes: Data collection, Refinement description
  • Version 2.0: 2023-11-15
    Changes: Atomic model, Data collection