6QDA

Leishmania major N-myristoyltransferase in complex with quinazoline inhibitor IMP-0000811


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.167 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Novel Thienopyrimidine Inhibitors of Leishmania N -Myristoyltransferase with On-Target Activity in Intracellular Amastigotes.

Bell, A.S.Yu, Z.Hutton, J.A.Wright, M.H.Brannigan, J.A.Paape, D.Roberts, S.M.Sutherell, C.L.Ritzefeld, M.Wilkinson, A.J.Smith, D.F.Leatherbarrow, R.J.Tate, E.W.

(2020) J Med Chem 63: 7740-7765

  • DOI: https://doi.org/10.1021/acs.jmedchem.0c00570
  • Primary Citation of Related Structures:  
    6QD9, 6QDA, 6QDB, 6QDC, 6QDD, 6QDE, 6QDF, 6QDG, 6QDH

  • PubMed Abstract: 

    The leishmaniases, caused by Leishmania species of protozoan parasites, are neglected tropical diseases with millions of cases worldwide. Current therapeutic approaches are limited by toxicity, resistance, and cost. N -Myristoyltransferase (NMT), an enzyme ubiquitous and essential in all eukaryotes, has been validated via genetic and pharmacological methods as a promising anti-leishmanial target. Here we describe a comprehensive structure-activity relationship (SAR) study of a thienopyrimidine series previously identified in a high-throughput screen against Leishmania NMT, across 68 compounds in enzyme- and cell-based assay formats. Using a chemical tagging target engagement biomarker assay, we identify the first inhibitor in this series with on-target NMT activity in leishmania parasites. Furthermore, crystal structure analyses of 12 derivatives in complex with Leishmania major NMT revealed key factors important for future structure-guided optimization delivering IMP-105 ( 43 ), a compound with modest activity against Leishmania donovani intracellular amastigotes and excellent selectivity (>660-fold) for Leishmania NMT over human NMTs.


  • Organizational Affiliation

    Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, London, U.K. W12 0BZ.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glycylpeptide N-tetradecanoyltransferase421Leishmania majorMutation(s): 0 
Gene Names: NMTLMJF_32_0080
EC: 2.3.1.97
UniProt
Find proteins for Q4Q5S8 (Leishmania major)
Explore Q4Q5S8 
Go to UniProtKB:  Q4Q5S8
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ4Q5S8
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.167 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.048α = 90
b = 90.414β = 111.97
c = 53.316γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALAdata scaling
REFMACphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2020-05-06
    Type: Initial release
  • Version 1.1: 2020-12-02
    Changes: Database references
  • Version 1.2: 2024-01-24
    Changes: Data collection, Database references, Refinement description