4MCB

H.influenzae TrmD in complex with N-(4-{[(1H-IMIDAZOL-2-YLMETHYL)AMINO]METHYL}BENZYL)-4-OXO-3,4-DIHYDROTHIENO[2,3-D]PYRIMIDINE-5-CARBOXAMIDE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.94 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.180 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Selective Inhibitors of Bacterial t-RNA-(N(1)G37) Methyltransferase (TrmD) That Demonstrate Novel Ordering of the Lid Domain.

Hill, P.J.Abibi, A.Albert, R.Andrews, B.Gagnon, M.M.Gao, N.Grebe, T.Hajec, L.I.Huang, J.Livchak, S.Lahiri, S.D.McKinney, D.C.Thresher, J.Wang, H.Olivier, N.Buurman, E.T.

(2013) J Med Chem 56: 7278-7288

  • DOI: https://doi.org/10.1021/jm400718n
  • Primary Citation of Related Structures:  
    4MCB, 4MCC, 4MCD

  • PubMed Abstract: 

    The tRNA-(N(1)G37) methyltransferase (TrmD) is essential for growth and highly conserved in both Gram-positive and Gram-negative bacterial pathogens. Additionally, TrmD is very distinct from its human orthologue TRM5 and thus is a suitable target for the design of novel antibacterials. Screening of a collection of compound fragments using Haemophilus influenzae TrmD identified inhibitory, fused thieno-pyrimidones that were competitive with S-adenosylmethionine (SAM), the physiological methyl donor substrate. Guided by X-ray cocrystal structures, fragment 1 was elaborated into a nanomolar inhibitor of a broad range of Gram-negative TrmD isozymes. These compounds demonstrated no activity against representative human SAM utilizing enzymes, PRMT1 and SET7/9. This is the first report of selective, nanomolar inhibitors of TrmD with demonstrated ability to order the TrmD lid in the absence of tRNA.


  • Organizational Affiliation

    Departments of Chemistry, ‡Biosciences and §Discovery Sciences, Infection Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
tRNA (guanine-N(1)-)-methyltransferase
A, B
246Haemophilus influenzae Rd KW20Mutation(s): 0 
Gene Names: HI_0202trmD
EC: 2.1.1.228
UniProt
Find proteins for P43912 (Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd))
Explore P43912 
Go to UniProtKB:  P43912
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP43912
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
21W
Query on 21W

Download Ideal Coordinates CCD File 
E [auth A],
H [auth B]
N-(4-{[(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-5-carboxamide
C19 H18 N6 O2 S
RLANZYKQCHLLJS-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A],
G [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
C [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
F [auth B]ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
21W Binding MOAD:  4MCB IC50: 1500 (nM) from 1 assay(s)
PDBBind:  4MCB IC50: 1500 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.94 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.180 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.158α = 90
b = 74.158β = 90
c = 119.288γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
JDirectordata collection
PROCESSdata reduction
AMoREphasing
BUSTERrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-09-04
    Type: Initial release
  • Version 1.1: 2013-10-09
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations