5MU6

Human N-myristoyltransferase (NMT1) with Myristoyl-CoA and IMP-1088 inhibitor bound


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.88 Å
  • R-Value Free: 
    0.247 (Depositor), 0.250 (DCC) 
  • R-Value Work: 
    0.204 (Depositor), 0.210 (DCC) 
  • R-Value Observed: 
    0.206 (Depositor) 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted MYAClick on this verticalbar to view detailsBest fitted KFKClick on this verticalbar to view details

This is version 1.3 of the entry. See complete history


Literature

Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus.

Mousnier, A.Bell, A.S.Swieboda, D.P.Morales-Sanfrutos, J.Perez-Dorado, I.Brannigan, J.A.Newman, J.Ritzefeld, M.Hutton, J.A.Guedan, A.Asfor, A.S.Robinson, S.W.Hopkins-Navratilova, I.Wilkinson, A.J.Johnston, S.L.Leatherbarrow, R.J.Tuthill, T.J.Solari, R.Tate, E.W.

(2018) Nat Chem 10: 599-606

  • DOI: https://doi.org/10.1038/s41557-018-0039-2
  • Primary Citation of Related Structures:  
    5MU6, 5O48, 5O4V, 5O6H, 5O6J

  • PubMed Abstract: 

    Rhinoviruses (RVs) are the pathogens most often responsible for the common cold, and are a frequent cause of exacerbations in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we report the discovery of IMP-1088, a picomolar dual inhibitor of the human N-myristoyltransferases NMT1 and NMT2, and use it to demonstrate that pharmacological inhibition of host-cell N-myristoylation rapidly and completely prevents rhinoviral replication without inducing cytotoxicity. The identification of cooperative binding between weak-binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking and conformational control over linker geometry. We show that inhibition of the co-translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, to deliver a low nanomolar antiviral activity against multiple RV strains, poliovirus and foot and-mouth disease virus, and protection of cells against virus-induced killing, highlighting the potential of host myristoylation as a drug target in picornaviral infections.


  • Organizational Affiliation

    National Heart & Lung Institute, Imperial College London, London, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glycylpeptide N-tetradecanoyltransferase 1
A, B
391Homo sapiensMutation(s): 0 
Gene Names: NMT1NMT
EC: 2.3.1.97 (PDB Primary Data), 2.3.1 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for P30419 (Homo sapiens)
Explore P30419 
Go to UniProtKB:  P30419
PHAROS:  P30419
GTEx:  ENSG00000136448 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP30419
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MYA
Query on MYA

Download Ideal Coordinates CCD File 
C [auth A],
H [auth B]
TETRADECANOYL-COA
C35 H62 N7 O17 P3 S
DUAFKXOFBZQTQE-QSGBVPJFSA-N
KFK
Query on KFK

Download Ideal Coordinates CCD File 
G [auth A],
L [auth B]
1-[5-[3,4-bis(fluoranyl)-2-[2-(1,3,5-trimethylpyrazol-4-yl)ethoxy]phenyl]-1-methyl-indazol-3-yl]-~{N},~{N}-dimethyl-methanamine
C25 H29 F2 N5 O
SOXNKJCQBRQUMS-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
J [auth B],
K [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
D [auth A],
I [auth B]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
KFK BindingDB:  5MU6 IC50: 1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.88 Å
  • R-Value Free:  0.247 (Depositor), 0.250 (DCC) 
  • R-Value Work:  0.204 (Depositor), 0.210 (DCC) 
  • R-Value Observed: 0.206 (Depositor) 
Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.73α = 90
b = 180.73β = 90
c = 58.99γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
Aimlessdata scaling
PHASERphasing
REFMACrefinement
PHENIXrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted MYAClick on this verticalbar to view detailsBest fitted KFKClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
United Kingdom--

Revision History  (Full details and data files)

  • Version 1.0: 2018-02-14
    Type: Initial release
  • Version 1.1: 2018-05-23
    Changes: Data collection, Database references
  • Version 1.2: 2018-07-04
    Changes: Data collection, Database references
  • Version 1.3: 2024-01-17
    Changes: Data collection, Database references, Derived calculations, Refinement description